1Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, USA
2Yale School of Medicine, Department of Psychiatry, New Haven, USA
*Corresponding author:
Roger L. Papke
Department of Pharmacology and Therapeutics
University of Florida College of Medicine, Gainesville, FL 32610, USA E-mail: rlpapke@ufl.edu
Received May 04, 2012; Accepted May 05, 2012; Published May 07, 2012
Citation: Papke RL, Picciotto MR (2012) Nicotine Dependence and
Depression, What is the Future for Therapeutics? J Addict Res Ther
3:e105. doi:10.4172/2155-6105.1000e105
There is a complex relationship between nicotine use, subsequent
nicotine dependence, and depression. Nicotine delivered by patch
reportedly has antidepressant properties, even in non smokers [1], but
the incidence of depression in smokers is high, and higher still in people
attempting to quit smoking. Sorting out cause and effect with such
observations is very difficult. One of the earliest theories on the etiology
of depression was the cholinergic hypothesis proposed by Janowsky
[2], which was based largely on the effects of cholinesterases inhibitors
on mood, suggesting a relationship between a hypercholinergic state
and depression. Since the early work by Janowsky, the concept of
a hypercholinergic state in depression has been extended to apply
to CNS muscarinic, and more recently, nicotinic receptor function.
Here, with the additional consideration of nicotinic Acetylcholine
Receptors (nAChR), we have the confounding conundrums of the
mixed activating and desensitizing properties of nicotine [3] and the
well-documented up-regulation of brain nAChR with chronic nicotine
[4,5]. To what degree is the hypercholinergic state hypothesized by
Janowsky related to increased acetylcholine, affecting both nicotinic
and muscarinic tone, or to upregulated receptor function in one system
or in both systems?
The current therapies for depression are generally thought to work
through the modulation of the biogenic amines, primarily serotonin and,
to a lesser degree, nor-epinephrine. However, many antidepressants
have anticholinergic activities as well. The antimuscarinic effects of
antidepressants, most notable for tricyclics, are generally considered
adverse side effects. However, the original work of Janowsky, and
more recent work by Drevets [6], would suggest that such activity
would also be part of their therapeutic efficacy. Numerous studies have
also implicated antinicotinic activity as part of the profile for specific
antidepressants and the antidepressant bupropion is approved for
smoking cessation. Likewise, the smoking cessation drug varenicline
has been shown to have antidepressant activity in animal models [7],
with suggestive data for humans as well [8]. These two compounds
hypothetically use two different pharmacologic approaches for
down-regulating the activity of select brain nAChR, noncompetitive
antagonism for bupropion and partial agonism for varenicline.
The efficacy of bupropion, both as an antidepressant and as a
smoking cessation aid, may be at the heart of the mysterious connection
linking nicotine dependence and depression, since bupropion is both
a modulator of biogenic amines [9] and a nAChR antagonist [10]. It
was initially assumed that bupropion’s efficacy as a smoking cessation
agent was due to the management of depression associated with
nicotine withdrawal and therefore related to its blockade of biogenic
amine reuptake [11]. Ironically, it might now be hypothesized that
its antidepressant activity is also associated with its block of nAChRs.
This leaves an unresolved paradox that might only be resolved when
we can better appreciate the underlying, and likely heterogeneous,
causes for major depressive disorder and why individual patients vary
so greatly in their responsiveness to specific agents. For particular
patients responding to bupropion therapy for depression, the relative
importance of the two aspects of the drug’s action on biogenic amines
or on nAChR may differ.
Is there a future for antidepressant therapies that rely exclusively on a nicotinic mechanism, and if so, will they be useful as monotherapy or
fill a gap for adjunct therapies to be combined with more conventional
antidepressants for refractory patients? The latter possibility was just
put to a test with the combination of two specific agents, TC-5214, a
stereoisomer of the classic neuronal nAChR antagonist mecamylamine,
and citalopram, a popular serotonin reuptake inhibitor. A series of
Phase 3 trials with these two agents were recently reported to have failed
to show positive effects on their primary treatment endpoints. Do these
failed trials mean an end for the development of anti-nicotinic drugs
for depression? Several points could be argued against that conclusion.
Was mecamylamine the right choice for a down-regulator of
nAChR function? Was TC-5214, the s-isomer, the best choice compared
to the r-isomer or the racemic drug? Was citalopram the best choice
for the drug to pair with mecamylamine in a combination therapy?
Mecamylamine is strictly a nAChR antagonist, and more effective
at inhibiting putative off-target α3β4 receptor subtypes associated
with the function of the autonomic nervous system [12] than for the
most likely target receptors, high affinity α4β2 nAChR in the brain.
This factor alone might have limited the usefulness of mecamylamine,
forcing dosages to be kept low in order to avoid autonomic side effects.
An initial characterization of the two mecamylamine stereoisomers
showed little reason to commend one over the other as a nAChR
antagonist [13]. However, a subsequent study presented data suggesting
the s-isomer (TC-5214) might have mixed effects, both potentiating
and then at higher concentrations inhibiting a specific high sensitivity
α4β2 receptor subtype that is believed to be up-regulated by chronic
nicotine [14]. Notwithstanding that the putative potentiating activity
for high sensitivity α4β2 receptors is not reproducible in a standard
expression system (Xenopus oocytes, R. Papke, unpublished), it is
unclear why potentiating activity for a target receptor subtype would
be a desirable feature when the intended therapeutic mechanism is to
inhibit that receptor subtype. Nonetheless, the s-isomer appeared to
have a better activity profile in a series of animal studies and believed to
be predictive for antidepressant efficacy, as well as a better safety profile
than the r-isomer [15].
Would it have been better to pursue mecamylamine as a
monotherapy than as an augmentation to a Selective Serotonin
Reuptake Inhibitor (SSRI)? A primary rationale for combination
therapies is to use two drugs with different mechanisms and therefore
hopefully additive effects. This would have been a good rationale for
combining TC-5214 with citalopram and supported by other studies combining mecamylamine with SSRIs [16]. However, contradictory
results have been reported for mecamylamine in combination with
citalopram in animal studies [17,18].
Another rationale for combination therapies, one that has
already been demonstrated to be applicable to mecamylamine, is to
use a second drug to manage the side effects produced by a primary
therapeutic agent. Mecamylamine was previously shown in small scale
trials to have efficacy for the treatment of Tourette’s syndrome [19],
an observation which led to its use in a larger trial as a monotherapy.
The larger trial failed [20], and in retrospect the efficacy in the
earlier trials was judged to be due to mecamylamine’s suppression of
hypercholinergic side effects associated with concomitant antipsychotic
medications. Citalopram is considered to have few cholinergic side
effects, while older antidepressants, most notably the tricyclics, have
significant cholinergic side effects, which are usually classified as anti
muscarinic. It might be hypothesized that nicotinics and muscarinics
may be doing complementary things under normal conditions, so that
something with antimuscarinic effects might therefore have a pronicotinic
activity that could have been targeted by the mecamylamine.
Moreover, antimuscarinic activity might induce a neuro-adaptive
upregulation of cholinergic tone, which would also have pronicotinic
effects. Therefore, it might have been more useful to pair TC-5214 with
a tricyclic antidepressant. Side effects often limit the therapeutic dosing
of antidepressants, and therefore better management of side effects
might permit better therapeutic effects for the primary agent. As noted
above, partial agonists present an alternative approach for managing
hyperactivity of a neurotransmitter system. Partial agonists may be
designed for significant selectivity for specific receptor subtypes. Such
profiles can be highly variable and potentially very effectively tuned
to function as agonists for some receptor subtypes and effectively as
competitive antagonists of other subtypes. For example, varenicline
and cytisine, two agents currently in use as smoking cessation aids,
are often characterized as α4β2 partial agonists [21,22]. The α4β2
nAChR of the brain are generally accepted as a primary target for
both smoking behavior and hypercholinergic activity in depression.
However, the characterization of varenicline and cytisine as selective
α4β2 partial agonists is not really correct, since both of these agents
have significant activity for probable off-target receptors, such as
ganglionic α3β4 receptors and the low affinity α7 receptors of the brain
that are associated with cognition and neuropsychiatric disorders [22-24]. Additionally, as we are guided by evaluations of efficacy in animal
models, we must also account for differences that may exist between
the activity profiles of select agents for the receptors in the study animal
and in humans. In fact, it has recently reported that the activity of
varenicline and cytisine differ significantly for the ganglionic receptor
analogs of rodents and humans [25].
In summary, the disappointing clinical results with TC-5214
should serve primarily to guide, rather than to discourage, future
drug development in this area, especially since such work may lead to
improved therapies for smoking cessation as well as for the potential
management of major depressive disorders. It is possible that new
nAChR antagonists with improved on-target activity for CNS receptors
may be developed and paired with more appropriate primary agents
in order to lead to positive outcomes for the treatment of depression.
Additionally, it seems likely that the future of anti-nicotinic therapies,
both as smoking cessation aids and as potential therapies for depression,
will come from the development of new, truly selective, partial agonists
that will produce a down-regulation of α4β2* receptor function with
little or no activity for other nAChR subtypes. Recent publications
indicate that such drugs are likely to become available [26,27], and the tools are available to confirm that agents that are active in animal
models will be likely to have similar activity profiles for human receptors
with therapeutically relevant experimental protocols [28]. However,
the challenges for the development of therapeutics in these areas are
great. While the majority of patients suffering from major depressive
disorder will response to one of the available pharmacotherapies, until
we achieve a better understanding of the heterogeneity likely to exist
in the causes of depression, it is probable that we will have to continue
to rely on slow empirical determinations of whether each patient is
matched to an effective therapy. Likewise, in order to design smoking
cessation therapies with more than the marginal 15-20% efficacy of
existing therapeutics, such as bupropion, varenicline, and cytisine,
we need to improve our understanding of the root causes for nicotine
dependence and smoking relapse.
Fedorov N, Moore L, Gatto G, Jordan K, Bencherif M (2007) Differential effects of TC-5214 [S-(+)-mecamylamine] and TC-5213 [R-(-)-mecamylamine] at low and high sensitivity human alpha4beta2 nicotinic receptors and in animal models of depression and anxiety, in 37th Annual Meeting of the Society for Neuroscience, San Diego, CA.
Stokes C, Papke RL (2012) Use of an alpha3-beta4 nicotinic acetylcholine receptor subunit concatamer to characterize ganglionic receptor subtypes with specific subunit composition reveals species-specific pharmacologic properties. Neuropharmacology.
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