Amitifadine is a antidepressant drug currently in stage 3 clinical trials.
Amitifadine (formerly EB-1010) is a triple reuptake inhibitor with the greatest potency towards serotonin reuptake (5-HT), half as much towards norepinephrine reuptake (NE) and one eighth towards dopamine reuptake (DA). This 1 to 2 to 8 ratio approximates the pharmacology of the two-product combination of citalopram and bupropion found to have favorable outcomes in STAR*D, a 4,000 patient study conducted by the Federal Government’s National Institute of Mental Health.
Introduction to Amitifadine
Amitifadine, also known as DOV 21,947 or EB-1010, is an antidepressant drug being developed by Euthymics Bioscience Inc. which is currently in clinical trials. It is a so-called triple re/uptake inhibitor (TUI) or SNDRI.
Amitifadine acts on three neurotransmitters—serotonin, norepinephrine and dopamine—in a ratio of 1 to 2 to 8—and is intended to increase antidepressant efficacy while reducing the adverse effects that can limit compliance with antidepressants, including weight gain, sexual dysfunction and impaired cognition.
Results of a previous phase 2 trial published last year in the Journal of Psychiatric Research by Pierre Trân, M.D., Euthymics' Chief Medical Officer, and colleagues showed that at the end of the 6-week double-blind treatment, estimated mean change from baseline in MADRS was statistically superior for amitifadine compared to placebo with an overall statistical effect size of −0.601 (Cohen's d). Amitifadine was well tolerated, without the weight gain or sexual dysfunction associated with the most common pharmacological treatments for depression.
Using Amitifadine
Ways of Administration
Effects of Amitifadine
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 anti-depressant-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.
Results in a small clinical trial indicated that amitifadine had statistically significant antidepressant effects and was well tolerated.
In view of the safety profile of amitifadine in humans, including low risk for weight gain, lack of sexual side effects, and low potential for abuse, we hypothesize that amitifadine will be effective in treating co-occurring alcoholism and depression.Combinations with Amitifadine
Different Uses for Amitifadine
Possible alcoholism treatment.
Amitifadine, a triple monoamine uptake inhibitor, reduces binge drinking and negative affect in an animal model of co-occurring alcoholism and depression symptomatology.
The co-occurrence of alcoholism and depression is highly prevalent and difficult to treat. In an animal model of binge drinking that exhibits abstinence-induced behaviors reminiscent of negative affective states, the triple monoamine uptake inhibitor, amitifadine, produced a selective, dose dependent attenuation of binge drinking. Amitifadine also reversed abstinence-induced increases in the intracranial self-stimulation threshold, a model of anhedonia, and immobility in the forced swim test, reflecting behavioral despair. In view of the safety profile of amitifadine in humans, including low risk for weight gain, lack of sexual side effects, and low potential for abuse, it is hypothesized that amitifadine will be effective in treating co-occurring alcoholism and depression.
Chemistry of Amitifadine
Column 1 Column 2 Systematic(IUPAC) name: (1R,5S)-1-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0] hexane Synonyms: DOV 21,947, EB-1010, (1R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane Molecular Formula: C11H11Cl2N Molar mass: 228.12 g/mol [1] CAS Registry Number: 410074-73-6 Melting Point: ? Boiling Point: ? Flash Point: no data Solubility: Additionnal data: Notes:
More Amitifadine Sections
Euthymics Bioscience, Inc. today announced completion of enrollment in the advanced clinical study of its lead product candidate amitifadine (formerly called EB-1010), a novel serotonin-preferring triple reuptake inhibitor for the treatment of major depressive disorder (MDD). The TRIADE (Triple Reuptake Inhibitor Anti-Depressant Effects) study is a phase 2b/3a clinical trial designed to assess the safety and efficacy of amitifadine. A total of 342 MDD patients were randomized at 39 centers in the US. Top-line results are expected by the end of 1Q 2013.
Amitifadine acts on three neurotransmitters—serotonin, norepinephrine and dopamine—in a ratio of 1 to 2 to 8—and is intended to increase antidepressant efficacy while reducing the adverse effects that can limit compliance with antidepressants, including weight gain, sexual dysfunction and impaired cognition. TRIADE evaluated amitifadine for patients with MDD who did not respond adequately to one and only one course of first-line antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion or tricyclic antidepressants, some of the most commonly used medications in the $11 billion US antidepressant market.
"We are developing amitifadine for its potential as a broad spectrum antidepressant for primary care physicians and psychiatrists to use after the patient fails to respond to a course of first-line antidepressants," said Anthony A. McKinney, President and CEO of Euthymics. "TRIADE is designed to support use of amitifadine as the next step once patients have failed initial therapy. This 'first of second-line' approach proposes amitifadine as a monotherapy for use after first-line generic antidepressants have failed but before more complex and costly drug combinations are tried."
TRIADE has incorporated advanced clinical trial techniques to reduce placebo effects and ensure quality control in patient selection. A novel clinical trial design, the Sequential Parallel Comparison Design (SPCD) was used to enhance the drug-placebo separation signal by reducing placebo response. Approximately half of all depression trials fail due to excessive placebo response and the SPCD was designed to address this intractable issue. SPCD has been previously used in three trials for depression and in each case the placebo response was substantially less, usually half of the typical 35-40% placebo response rate from typical antidepressant trials.
Amitifadine
References
http://www.ncbi.nlm.nih.gov/pubmed/22884707
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
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
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
http://euthymics.com/our-programs/mdd-and-eb-1010/
[2]Calculated from Atomic Weights of the Elements, 2007