Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience[1][2] It was under development for the treatment of major depressive disorder, but in May 2013, it was reported that the drug failed to show superior efficacy to placebo in a phase IIb/IIIa clinical trial.[3] It was suggested that this may have been due to the drug being underdosed.[3] In September 2017, development of amitifadine for the treatment of major depressive disorder was finally officially discontinued.[1] As of September 2017, it is still listed as being under development for the treatment of alcoholism and smoking withdrawal.[1]

Clinical data
Pronunciation(/æmɪˈtɪfədn/ am-i-TIF-ə-deen)
Other namesDOV-21,947; EB-1010
Legal status
Legal status
CAS Number
PubChem CID
Chemical and physical data
Molar mass228.118 g/mol g·mol−1
3D model (JSmol)


Ki values for SERT, NET, and DAT of amitifadine are 99 nM, 262 nM, and 213 nM.[2] The IC50 values for serotonin, norepinephrine and dopamine uptake are 12, 23 and 96 nM, respectively

Amitifadine and isomers
Compound Uptake (IC50, nM) Binding (Ki, nM)
Amitifadine 12 23 96 100 260 210
DOV-216,303 14 20 78 190 380 190
DOV-102,677 130 100 130 740 1000 220

Amitifadine reduces the duration of immobility in the forced swim test in rats with an oral minimum effective dose (MED) of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. Amitifadine also produces a dose-dependent reduction in immobility in the tail suspension test, with an oral MED of 5 mg/kg. In microdialysis studies, amitifadine increased extracellular levels of serotonin, norepinephrine and dopamine in brain regions and did not induce hyperactivity in rats.[4] Results in a small clinical trial indicated that amitifadine had statistically significant antidepressant effects and was well tolerated.[5]


Amitifadine is the (+)-enantiomer of DOV-216,303, and its (−)-enantiomer is DOV-102,677.


  1. "Amitifadine". AdisInsight. Retrieved 26 February 2017.
  2. Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. (2003). "Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor". European Journal of Pharmacology. 461 (2–3): 99–104. doi:10.1016/S0014-2999(03)01310-4. PMID 12586204.
  3. "Archived copy" (PDF). Archived from the original (PDF) on 2017-09-24. Retrieved 2017-06-12.CS1 maint: archived copy as title (link)
  4. Golembiowska, K.; Kowalska, M.; Bymaster, F. P. (2012). "Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity". Synapse. 66 (5): 435–444. doi:10.1002/syn.21531. PMID 22213370.
  5. Tran, P.; Skolnick, P.; Czobor, P.; Huang, N. Y.; Bradshaw, M.; McKinney, A.; Fava, M. (2012). "Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial". Journal of Psychiatric Research. 46 (1): 64–71. doi:10.1016/j.jpsychires.2011.09.003. PMID 21925682.
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