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Everything and SNDRI: Amitifadine on the Antidepressant Frontier
Anita Marie Scotti
PHCY 503: Molecular Foundations of Drug Action
Profs. Jarstfer, Singleton, & Fuller
November 6, 2015
Depressive disorders, including major depressive disorder (MDD), are among the leading causes of
disease burden and disability across the globe, with decennial reports showing a trajectory of severity that will
likely promote them from the second leading cause, as they were in the 2010 Global Disease Burden study, to
the first in a few short decades.1,2 The compound amitifadine (Fig. 1), formerly known as DOV 21947 and
presently in Phase IIb/IIIa drug trials led by Euthymics Bioscience, Inc., is a promising triple reuptake inhibitor
on the forefront of a new wave of antidepressants being specifically designed to tackle MDD and other
depressive disorders for which current treatments are ineffective in about 30% of sufferers.2,3
With a lifetime prevalence of 16.2%, major depressive disorder is a common personally and socially
debilitating condition.2,3 MDD is syndromic and the current understanding of its pathophysiological basis for is
incomplete. Clusters of symptoms are often recurrent and often they encompass extreme opposites, making
for seemingly contradictory phenotypes. Symptoms of MDD may include sleep disturbances (hypersomnia or
insomnia), appetite and weight disturbances (anorexia or hyperphagia; weight loss or gain), agitated or
retarded movement, emotional lability or flattened affect, sadness, hopelessness, loss of pleasure, fatigue,
cognitive dysfunction, impaired memory, motivation, and concentration, as well as an increased likelihood of
suicidality.2-7 The most commonly prescribed pharmacotherapies for MDD fall within the classes of monoamine
oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and monoamine transporter reuptake inhibitors,
with the latter being considered first-line treatment.2,5,10
A biochemically-based theory, known as the monoamine hypothesis, posits that depression is the result
of deficiency, hypoactivity, or imbalance of the monoamine neurotransmitters serotonin (5-HT) and
norepinephrine (NE) within the brain (Fig. 2).2,3,6 In general, all antidepressants with clinical efficacy act on
serotonergic or noradrenergic pathways or both, attempting to preserve or increase the level of
neurotransmission by either preventing the degradation of the monoamine signaling molecules or by increasing
the amount available for signaling within the synaptic cleft through blockade of the transporter proteins that
take neurotransmitters back up into the presynaptic neuron from whence they were released (Fig. 3).7,8 Much
of what is known about the complex mental phenomenon of depression has come as the result of research into
the biochemistry behind efficacious antidepressants. The “first” generation MAOIs and TCAs were derived on
account of the serendipitous antidepressant side-effects of failed tuberculosis (isoniazid) and anti-psychotic
(imipramine) medications, but their efficacy was soon linked to their action on serotonin and norepinephrine.3
Deliberate efforts to rationally design drugs with structures that exploited this newfound understanding, and
which had less onerous side-effect profiles, led to drugs like fluoxetine, citalopram, paroxetine, sertraline, and
venlafaxine—selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs), or
serotonin and norepinephrine reuptake inhibitors (SNRIs).3,5,7,8 Since the advent of these oft-prescribed
selective monoamine transporter blockers, development of antidepressants has generally been variation on a
theme, with only small changes being made to existing structures in an effort to improve efficacy and safety.4
The use of MAOIs and TCAs is declining on account clinicians’ wariness of severe side-effect and
interaction potential with these drugs; SSRIs and those antidepressants with dual modes of action are the
favored treatments, with a growing body of evidence to suggest that multiple mechanisms of action make for
more effective antidepressants, but even these provide slow and incomplete relief to the majority of
patients.4,5,7 Residual symptoms often include anhedonia, a lack of pleasure in and motivation to enjoy formerly
rewarding activities, or sexual dysfunction.5,7,8 These symptoms implicate the involvement of dopaminergic
mesolimbic system responsible for the experience of motivation, pleasure, and reward.4,7,10 The successful
mitigation of these symptoms when the dopamine norepinephrine reuptake inhibitor (DNRI) bupropion is used
as a therapeutic adjunct to MAOI or SSRI therapies reinforces the idea that dopamine (Fig. 2) is also an
important mediator of depression.3,5,8,11 In fact, there is a high degree of interconnection between the
serotonergic, noradrenergic, and dopaminergic pathways in the brain (Fig. 4).7 This has led to a dopamine
corollary to the monoamine hypothesis of depression, as well as increased interest in the development of triple
reuptake inhibitors (TRIs); also known as serotonin, norepinephrine, and dopamine reuptake inhibitors
(SNDRIs); which are single small molecule agents effective at blocking serotonin transporters (SERTs),
norepinephrine transporters (NETs), and dopamine transporters (DATs) all at once (Fig. 5).8
The hope in developing triple reuptake inhibitors is that their action against the reuptake of all three
previously discussed neurotransmitters will provide some clinically relevant advantage over single- or dualacting agents, be it in the form of wider coverage of symptoms, reduced therapeutic lag, or better tolerability
and therefore better compliance.2,3,7,8,12 Each of these potential outcomes is supported in some way by
experimental or observational evidence that makes the viability of a broad spectrum antidepressant, like a TRI,
plausible.8,11 The chemical space defined by the compounds recently screened and patented for SNDRI
activity is highly diverse.8 There are few commonalities of structure between molecules like amitifadine and
other potential drugs of the class, with the exception of possession of at least one aromatic and one
heterocyclic ring (Fig.6).8 What seems to be more key to effective alleviation of depressive symptoms is the
ratio in which the TRI/SNDRI compound inhibits each of the three monoamine transporters.3,11,12,13 As
mentioned above, the combination of an SSRI and the DNRI bupropion is particularly efficacious at addressing
MDD symptoms. Amitifadine is perhaps the forerunner TRI on account of approximately replicating the ratio
established for the action of citalopram, an SSRI, in combination with bupropion, as defined by the Sequenced
Treatment Alternatives to Relieve Depression (STAR*D) study conducted by the National institutes of Mental
Health (NIMH).11,12 Serotonin-preferring amitifadine exhibits the following half-maximal inhibitory concentrations
(IC50) for SERT, NET, and DAT, respectively: 12 nM, 23 nM, and 96 nM.3 This translates to roughly a 1:2:8
ratio; amitifadine is most potent at the serotonin transporter, half as potent at the norepinephrine transporter,
and one eighth as potent at the dopamine transporter.3,11,12 Amitifadine is being positioned as a second-line
treatment after failure of one course of antidepressant therapy, but prior to the use of combination therapy.12,13
To date, amitifadine has been demonstrated to be effective at each of the monoamine transporters in in
vitro HEK 293 human embryonic kidney cell assays and in vivo animal models of depression, such as the
forced swim test and the tail suspension test in rats.10 Phase II studies in people have also shown amitifadine
to be effective in relieving MDD symptoms without the expected side-effects of SERT blockade—sexual
dysfunction and weight gain—and with minimal elevation of heart rate and blood pressure as is expected from
inhibition of NET.5, 11,12 There is some trepidation over the abuse potential amitifadine might have as a
consequence of its DAT inhibitory effects, but it is thought that the much slower onset and peak brain and
blood levels of the drug, as compared with the rapid onset of TRIs like cocaine, will almost eliminate this
possibility.3,4,5 While still a promising contender, a Phase IIb/IIIa study of amitifadine, called TRIADE, yielded
disappointing top line results in that amitifadine did not outpace the strong performance of the placebo
arm.4,8,12,13 This was not entirely unexpected, as the placebo effect is particularly robust with antidepressants,
and post hoc analyses suggested that amitifadine was under-dosed, given the excellent tolerability.4,12,13 A
New Drug Application (NDA) has not been filed with the Food and Drug Administration (FDA) for approval, and
further trials utilizing higher dosages may be forthcoming before that occurs. In any case, as with many of the
antidepressants which have come before it, amitifadine may prove to be more important for what it can teach
about the neurobiology and chemistry of depression as for its efficacy as an antidepressant. Only time will tell.
Figure 1: Amitifadine, (1R, 5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0.]hexane. Amitifadine is the (+)
optical enantiomer of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0.]hexane and is the more active of the two
racemates.
(Adapted from Shao L, Wei L, Qiong X, et al. Triple reuptake inhibitors: A patent review (2006-2012). Expert
Opin Therapeutic Patents. 2014; 24 (2): 131-154.)
Figure 2: Monoamine neurotransmitters implicated in depressive disorders. The neurotransmitters
serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are thought to be variously responsible for the
symptoms of major depressive disorder and other psychiatric illnesses by their absence, weakness, or
imbalance.
(Adapted from Singleton SF. Receptors as Drug Targets 2: Adrenergic GPC Agonists [presentation]. October
6, 2105: 9.)
Figure 3: Neurotransmission at the synapse: Signaling and inhibition of monoamines. The action of
antidepressants occurs either to inhibit MAO-A, the isoform which degrades neurotransmitters, or to inhibit the
monoamine transport proteins which take up the neurotransmitter back into the presynaptic neuron.
(Based on Perovic B, Jovanovic M, Miljkovic B, et al. Getting the balance right: Established and emerging
therapies for major depressive disorders. Neuropsych. Dis and Treatm. 2010; 10 (6): 343-364.)
Figure 4: Schematic overview of brain areas involved in major depressive disorder and their
(monoaminergic) connections. In green, noradrenergic projections. In red, serotonergic projections. In blue,
dopaminergic projections. Many publications support the finding that a high degree of connectivity exists
between monoaminergic neurons. +1 Excitatory; -: Inhibitory. BLA: Basolateral amygdala; BNST: Bed nucleus
of stria terminalis; CeA: Central amygdala; DR: Dorsal raphe nucleus; dGP: Dorsal globus pallidus; LC: Locus
coeruleus; MP: Median raphe nucleus; NAcs: Nucleus accumbens shell; NACC: Nucleus accumbens core;
dStriatum: Dorsal striatum; PFC: prefrontal cortex; PVN: Paraventricular nucleus of hypothalamus; SN:
Substantia nigra: VTA: Ventral tegmental area; VGP: Ventral globus pallidus.
(Taken from Prins J, Olivier B, & Korte M. Triple reuptake inhibitors for treating subtypes of major depressive
disorder: The monoamine hypothesis revisited. Expert Opin Investig Drugs. 2001; 20 (8): 1107-1130.)
-Attention
-Interest
DNRIs
Bupropion
Nomifensine
Methylphenidate
NRIs
Reboxetine
Atomoxetine
Viloxazine
Despiramine
DRIs
(none)
NOREPINEPHRINE
-Psychomotor
-Vigilance
-Anxiety
SNRIs
Venlafaxine
Duloxetine
Milnacipram
SNDRIs/TRIs
Amitifadine
-Mood
SEROTONIN
-Impulsivity
-Aggression
-Sleep
DOPAMINE
-Motivation
-Concentration
-Reward
-Sexuality
-Eating
SDRIs
(none)
SSRIs
Escitalopram
Citalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Figure 5: The state of the monoamine hypothesis of depression: monaminergic domains and selective
monoamine transporter reuptake inhibiting drugs.
(Based on Korte, SM, Prins J, Krajnc AM, et al. The many faces of major depression: It is time for personalized
medicine. Eur J Pharmacol. 2015; 753: 88-104. and on Guiard, BP. A new class of antidepressant drugs in the
treatment of psychiatric disorders: The triple reuptake inhibitors. In: Uehara, T, ed. Psychiatric Disorders—
Trends and Developments. InTech: 2011.)
Figure 6: Some examples of molecules with TRI/SNDRI behavior and cocaine for comparison. Cocaine
is a balanced TRI and may be said to be one of the progenitors of the class; several tropane analogs have
been derived from its structure with an eye toward use as TRIs. Other compounds include amphetaminederived analogs, piperidines, piperazines, and tetrahydroisoquinolines. Most TRIs contain at least one aromatic
ring, often more than one, and at least one heterocyclic ring.
(Adapted from Shao L, Wei L, Qiong X, et al. Triple reuptake inhibitors: A patent review (2006-2012). Expert
Opin Therapeutic Patents. 2014; 24 (2): 131-154.)
References
1. Ferrari AJ, Charlson FJ, Norman RE, et al. Burden of depressive disorders by country, sex, age, and
year: Findings from the global burden of disease study 2010. PLOS Med. 2013; 10 (11): 1-12.
http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001547. Accessed October 30,
2015.
2. Perovic B, Jovanovic M, Miljkovic B, et al. Getting the balance right: Established and emerging
therapies for major depressive disorders. Neuropsych. Dis and Treatm. 2010; 10 (6): 343-364.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938284/. Accessed October 30, 2015.
3. Prins J, Olivier B, & Korte M. Triple reuptake inhibitors for treating subtypes of major depressive
disorder: The monoamine hypothesis revisited. Expert Opin Investig Drugs. 2001; 20 (8): 1107-1130.
http://vb3lk7eb4t.search.serialssolutions.com/?sid=Entrez:PubMed&id=pmid:21682663. Accessed
October 30, 2015.
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Accessed November 1, 2015.
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medicine. Eur J Pharmacol. 2015; 753: 88-104. http://vb3lk7eb4t.search.serialssolutions.com.libproxy.
lib.unc.edu/?sid=Entrez:PubMed&id=pmid:25592320. Accessed October 30, 2015.
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reuptake inhibitors. In: Uehara, T, ed. Psychiatric Disorders—Trends and Developments. InTech: 2011.
http://www.intechopen.com/books/psychiatric-disorders-trends-anddevelopments/a-new-class-ofantidepressant-drugs-in-the-treatment-of-psychiatric-disorders-the-triplereuptake-in. Accessed, October
30, 2015.
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Therapeutic Patents. 2014; 24 (2): 131-154. http://vb3lk7eb4t.search.serialssolutions.com.libproxy.
lib.unc.edu/?sid=Entrez:PubMed&id=pmid:24289044. Accessed November 1, 2015.
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9.
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inhibitor. Eur J Pharmacol. 2003; 461: 99-104. http://vb3lk7eb4t.search.serialssolutions.com.
libproxy.lib.unc.edu/?sid=Entrez:PubMed&id=pmid:12586204. Accessed November 1, 2015.
11. Tran P, Skolnick P, Czobor, P, et al. 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. J Psychiatric Research. 2012; 46: 64-71. http://vb3lk7eb4t.search.
serialssolutions.com.libproxy.lib.unc.edu/?sid=Entrez:PubMed&id=pmid:21925682. Accessed October
30, 2015.
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Web site. http://euthymics.com/euthymics-bioscience/. Accessed October 30, 2015.
13. Euthymics Bioscience, Inc. A serotonin-preferring triple reuptake inhibitor for the treatment of major
depression. Euthymics Bioscience, Inc. Web site. http://euthymics.com/wpcontent/uploads/2012/10/White-Paper-Amitifadine-092612.pdf. Accessed October 30, 2015.