Norepinephrine–dopamine disinhibitor

Norepinephrine and dopamine disinhibitors (NDDIs) are a class of drugs which act at specific sites to disinhibit downstream norepinephrine and dopamine release in the brain.^[1]

Chemical structure of agomelatine (Valdoxan), the prototypical NDDI.

Agomelatine, an antidepressant which disinhibits norepinephrine and dopamine release in the frontal cortex by antagonizing 5-HT_2C receptors,^[2] was the first drug to be described as an NDDI.^[3] While many other drugs also antagonize 5-HT_2C receptors to some degree or another, they tend to be very non-specific in their actions, and as a result, the term "NDDI" has generally, though not always (for instance, fluoxetine has been called an NDDI in addition to SSRI due to its (weak) blockade of 5-HT_2C),^[4] been reserved for describing newer, more selective agents in which disinhibition of norepinephrine and dopamine release is their primary mechanism of action.

Another drug that has been referred to as an NDDI in the medical literature is flibanserin,^[5] which is approved as a treatment for hypoactive sexual desire disorder in premenopausal women.^[6] Flibanserin disinhibits norepinephrine and dopamine release in the prefrontal cortex by activating 5-HT_1A receptors in this area.^[7]

Aside from agomelatine, fluoxetine, flibanserin and mirtazapine,^[8] as of present, no other drugs have been described as NDDIs in the medical literature, despite the fact that many other existing drugs possess effects consistent with those of the definition of an NDDI. In any case, more drugs labeled specifically as NDDIs may be seen in the future.

See also

• Noradrenergic and specific serotonergic antidepressant (NaSSA)
• Serotonin antagonist and reuptake inhibitor (SARI)
• Serotonin modulator and stimulator (SMS)

References

1. Ian P. Stolerman (30 August 2010). Encyclopedia of Psychopharmacology. Springer. p. 105. ISBN 978-3-540-68698-9. Retrieved 23 April 2012.
2. Millan MJ, Gobert A, Lejeune F, et al. (September 2003). "The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways". The Journal of Pharmacology and Experimental Therapeutics. 306 (3): 954–64. doi:10.1124/jpet.103.051797. PMID 12750432. S2CID 18753440.
3. Stahl SM (October 2007). "Novel mechanism of antidepressant action: norepinephrine and dopamine disinhibition (NDDI) plus melatonergic agonism". The International Journal of Neuropsychopharmacology. 10 (5): 575–8. doi:10.1017/S1461145707008000. PMID 17681087. S2CID 15836774.
4. Stephen M. Stahl (27 March 2008). Depression and Bipolar Disorder: Stahl's Essential Psychopharmacology. Cambridge University Press. p. 80. ISBN 978-0-521-88663-5. Retrieved 23 April 2012.
5. Stephen M. Stahl, S. M. Stahl (17 March 2008). Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press. p. 658. ISBN 978-0-521-67376-1. Retrieved 23 April 2012.
6. Thorp J, Simon J, Dattani D, et al. (March 2012). "Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the DAISY study". The Journal of Sexual Medicine. 9 (3): 793–804. doi:10.1111/j.1743-6109.2011.02595.x. PMID 22239862.
7. Stahl SM, Sommer B, Allers KA (January 2011). "Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder". The Journal of Sexual Medicine. 8 (1): 15–27. doi:10.1111/j.1743-6109.2010.02032.x. PMID 20840530.
8. Felker A, Stahl SM, eds. (2009), "Alpha 2 Antagonists as Serotonin and Norepinephrine Disinhibitors (SNDIs) and Serotonin Antagonist/Reuptake Inhibitors (SARIs)", Stahl's Illustrated Antidepressants, Stahl's Illustrated, Cambridge: Cambridge University Press, pp. 83–96, doi:10.1017/9781139194457.006, ISBN 978-0-521-75852-9, S2CID 239220471, retrieved 2023-01-14