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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 2, February 2006
Contents
Recent Strategies for Potentiation and
Facilitation of Antidepressant Treatment
Guest Editor: Eliyahu Dremencov
Editorial Pp.
135
Recent Strategies for Potentiation and Facilitation
of Antidepressant Treatment: Introduction
Pp. 137
B. Lerer
[Abstract]
Pindolol Augmentation of Antidepressant Response Pp.
139-147
F. Artigas, A. Adell and P. Celada
[Abstract]
Catecholaminergic Strategies for the Treatment of Major Depression
Pp. 149-158
P. Tremblay and P. Blier
[Abstract]
Potentiation of Antidepressant-Like Activity with
Lithium: Mechanism Involved Pp. 159-163
F. Chenu and M. Bourin
[Abstract]
Modulation of Dopamine Transmission by 5HT2C
and 5HT3 Receptors: A Role in the Antidepressant
Response Pp. 165-175
E. Dremencov, Y. Weizmann, N. Kinor, I. Gispan-Herman and
G. Yadid
[Abstract]
Serotonin-Dopamine Interaction as a Focus of Novel
Antidepressant Drugs Pp. 177-185
E. Esposito
[Abstract]
Microdialysis Approach to Study Serotonin Outflow in Mice
Following Selective Serotonin Reuptake Inhibitors and Substance
P (Neurokinin 1) Receptor Antagonist Administration: A Review
Pp. 187-201
B.P. Guiard, L. Lanfumey and A.M. Gardier
[Abstract]
Basic Mechanisms of Augmentation of Antidepressant
Effects with Thyroid Hormone Pp. 203-210
T. Lifschytz, R. Segman, G. Shalom, B. Lerer, E. Gur,
T. Golzer and M.E. Newman
[Abstract]
General Articles
Preventing Type 2 Diabetes in High Risk Patients:
An Overview of Lifestyle and Pharmacological Measures
Pp. 211-228
E.N. Liberopoulos, S. Tsouli, D.P. Mikhailidis and M.S.
Elisaf
[Abstract]
Enhancing the Site-Specific Targeting of Macromolecular Anticancer
Drug Delivery Systems Pp. 229-235
M.F. Neerman
[Abstract]
Abstracts
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Editorial
It was my great honor and pleasure to be suggested for the
guest editing of the theme issue in Current Drug Targets
and to prepare this issue entitled “Recent strategies
for potentiation and facilitation of antidepressant treatment”.
Major depression is a severe and dangerous mental disorder
with a lifetime prevalence of 20%. Throughout over 50 years
of research and drug development, different classes of medications
were developed and showed efficacy in the treatment of major
depression. However, the main limitations of most antidepressant
drugs are a long delay between the beginning of treatment
and the onset of the therapeutic effect of the treatment,
a high percentage of patients do not respond to the treatment
and a high risk of rapid relapse to depression even after
effective treatment.
Therefore, understanding the mechanisms of action of antidepressant
drugs and developing new strategies for potentiation and facilitation
of the treatment of depression is one of the main targets
of current psychopharmacological research. The aim of the
issue was to summarize the current research in the area of
neuropharmacological mechanism of antidepressant response
and novel strategies used to enhance it.
I would like to thank to the authors of the Issue for their
outstanding review manuscripts in their area of expertise,
such as augmentation and facilitation of antidepressant treatment
by pindolol, thyroid hormone, lithium or neurokenin, catecholaminergic
strategies for the treatment of major depression and the role
of serotonin-dopamine interaction in the antidepressant response.
Especial acknowledgement should be given to my mentors, Michael
E. Newman, Ph.D., Gal Yadid, Ph.D., and Pierre Blier, M.D.,
Ph.D., for their help and guidance during the Issue preparation,
to Bernard Lerer, M.D. for his introduction to the Issue,
to the Editor-in-chief, Francis J. Castellino, Ph.D., for
his kind invitation, to the reviewers, and to the Issue Manager,
Ms. Saima Ghaffar Rao, for coordinating the entire project.
Eliyahu Dremencov, Ph.D.
Issue Editor
Departement of Bioinformatics and Biotechnology
Jerusalem College of Technology, Israel, and
University of Ottawa Institute of Mental
Health Research, Ontario, Canada
E-mail: edremenc@rohcg.on.ca
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Recent Strategies for Potentiation and Facilitation
of Antidepressant Treatment: Introduction
B. Lerer
Depression is one of the major challenges facing clinical
medicine. Unipolar depression was ranked fifth among the leading
causes of disability worldwide in 2000 and projections indicate
that by 2020 it will be ranked second only to ischemic heart
disease [1]. Recognition and effective treatment of depression
is an important concern. Data from the US National Comorbidity
Survey indicate that almost half of those who suffer from
depression go untreated and that treatment is adequate in
only about 41% of cases [2].
Treatment approaches for depression that are supported by
evidence from randomized, controlled trials include antidepressant
drugs and specific psychotherapeutic approaches based on interpersonal
or cognitive-behavioral techniques. The data supporting efficacy
of antidepressant drugs are considerable and this modality
is the most widely used, for this reason and because it is
accessible to clinicians who are not psychiatrists and do
not have expertise in psychotherapy. Has the efficacy of antidepressant
medication increased appreciably since the first drugs of
this type were introduced almost half a century ago? Response
rates to active drug and placebo in controlled trials of antidepressants
suggest that there has been little change in this regard.
While response to active drug and placebo varies, a differential
of 20-30% between active drug and placebo remains constant
over scores of trials [3]. Since about 40% of responders to
active drug in antidepressant trials could well be placebo
responders, the true efficacy of currently available medications
is a matter of serious concern.
These considerations lead to the conclusion that an important
challenge facing contemporary psychopharmacology is to develop
antidepressant drugs that are effective in the ~40% of patients
who do not respond to current treatment. This will require
novel concepts beyond the current templates for drug development
that are essentially based on the mechanism of action of existing
agents. Whether blockbuster approaches based on the development
of “one size fits all” agents are the correct
direction is open to serious debate. Progress in the development
of new drugs could well depend on phenomenological dissection
of clinical subtypes and the identification of core, drug
responsive diagnostic entities. Pharmacogenetic approaches
could prove pivotal in this regard [4]. A further challenge
that is as yet unmet is the delay 2-4 weeks in onset of action
of antidepressants and the lengthy period of 6-8 weeks required
for drugs to be fully effective. There is very little evidence
to suggest that any of the currently available drugs act faster
than the others and this latency of effect is a major difficulty
facing clinicians who treat depressed patients.
On this background, the current issue of explores the pivotally
important strategy of supplementation of antidepressant action
and is most timely. The concept underlying this collection
of papers is that addition of a second therapeutic agent to
an antidepressant drug can have augmenting or accelerating
effects. Augmentation implies an increase in efficacy i.e.
a stronger therapeutic effect, which would convert non- or
partial responders to full responders. Accelerating effects
imply an earlier onset of action and more rapid achievement
of maximal therapeutic action. Both these objectives are fully
congruent with the major challenges facing antidepressant
drug development. Supplementary treatments currently being
explored involve harnessing neurotransmitter systems other
than those acted upon by the primary antidepressant drug (such
as dopamine), stimulating or blocking mechanistically relevant
receptors whose effect is to enhance the action of the primary
agent (such as 5-HT1A receptors) or the addition of substances
for which there is clinical evidence but whose mechanism of
action in depression is not fully understood (such as triiodothyronine).
From the point of view of therapeutics two drugs may well
be better than one and the current series of papers seeks
to explore whether and how this might be so. In the clinic,
each additional agent carries with it further risks of adverse
effects, the potential for pharmacokinetic interactions and
problems with compliance, which are directly related to the
number of pills the patient has to take and the frequency
with which he needs to take them. Nevertheless, research on
strategies for potentiation and facilitation of antidepressant
treatment can have very great potential impact, at the clinical
level and also as a basis for the development of novel antidepressant
drugs based on the mechanisms identified.
REFERENCES
[1] Murray, C.J., Lopez, A.D. (1997) Lancet, 349,
1498-1504.
[2] Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz,
D., Merikangas, K.R., Rush, A.J., Walters, E.E., Wang, P.S.
(2003) JAMA, 289, 3095-3105.
[3] Davis, J.M., Wang, Z., Janicak, P.G. (1993) Psychopharmacol.
Bull., 29, 175-81.
[4] Lerer, B., Macciardi, F. (2002) Int. J. Neuropsychopharmacol.,
5, 255-275.
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Pindolol Augmentation of Antidepressant
Response
F. Artigas, A. Adell and P. Celada
Pindolol, a partial ß-adrenoceptor/5-HT1A
receptor antagonist was first used to accelerate the onset
of action of antidepressant drugs in 1994. Since then, it
has been used in more than a dozen controlled trials to examine
whether it can reduce the lag to clinical improvement, and/or
improve the clinical response in treatment-resistant patients.
A recent metaanalysis concluded that pindolol accelerates
the antidepressant response but does not increase the effectiveness
of SSRIs in unresponsive patients. Several studies have examined
the pharmacology of pindolol to clarify the neurobio-logical
basis of its clinical action. Pindolol was initially used
due to its ability to block 5-HT1A receptor-mediated
re-sponses and to enhance the neurochemical effects of SSRIs.
In transfected cells, however, pindolol is a weak (20-25%)
partial agonist at 5-HT1A receptors and, as such,
its actions greatly depend on the system used. In line with
this, other reports have also shown that pindolol can reduce
serotonergic cell firing when given alone.
Positron emission tomography (PET) scan studies have shown
that pindolol displays a preferential occupancy of pre- vs.
postsynaptic 5-HT1A receptors, although the overall
occupancy is lower than desirable, which suggests that higher
doses (e.g., 15 mg/day) may be more effective than the currently
used 7.5 mg daily dosage. However, given the complex pharmacology
of pindolol, it is hoped that new developments in this field
can proceed through the use of a) selective and silent 5-HT1A
receptor antagonists in combination with SSRIs, or b) dual
action agents (SSRI + 5-HT1A receptor block-ers).
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Catecholaminergic Strategies for the Treatment of
Major Depression
P. Tremblay and P. Blier
Although the selective serotonin reuptake inhibitors have
become the first line medications for the treatment of depression,
drugs primarily targeting the norepinephrine (NE) and/or the
dopamine catecholaminergic systems are also effective. These
include selective NE reuptake inhibitors, such as desipramine
and reboxetine, the NE releaser bupropion and the α2-adrenergic
antagonists mianserin and mirtazapine. Dopamine type 2 agonists
are also effective in treating depression, although they are
rarely used. Since the NE, dopamine and serotonin systems
have reciprocal inter-actions, it is virtually impossible
to act on a specific neuronal element without affecting in
a cascade effect the two other systems. In this review, the
primary actions of the catecholaminergic strategies upon their
acute and long-term administration are described, as well
as their impact on other systems. Their use in treatment-resistant
depressed patients is also addressed.
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Potentiation of Antidepressant-Like Activity with
Lithium: Mechanism Involved
F. Chenu and M. Bourin
In the last decade, many augmentation strategies have been
developed to increase the activity of antidepressant drugs
or to reduce their long onset of action by acting on different
targets. One of the first augmentation strategy used in psychiatric
disorders is coadministration of lithium and antidepressant
drugs. However, the underlaying mechanism of action involved
in the potentiatory effect of lithium is still unclear and
many hypotheses have been suggested such as activity on BDNF,
ACTH, thyroid hormones and serotonin neurotransmission. All
these systems being embedded in each other, we focused on
the 5-HT neurotransmission-increase induced by lithium treatment.
Based on neuro-biochemical and behavioral results we tried
to better understand its mechanism of action and we concluded
that effect of lithium on 5-HT neurotransmission could be
linked to a partial agonist activity on 5-HT1B
autoreceptors, or to a modulatory activity on these receptors,
located in the cortical area in the case of a short term treatment,
or in the hippocampus in the case of a long term treatment.
We also suggested that the anti-manic effect of lithium was
linked to this activity on 5-HT1B receptors, occurring
this time on 5-HT1B postsynaptic (heteroreceptors
on dopaminergic pathways) receptors levels.
[Back to top]
Modulation of Dopamine Transmission by 5HT2C
and 5HT3 Receptors: A Role in the Antidepressant
Response
E. Dremencov, Y. Weizmann, N. Kinor, I. Gispan-Herman and
G. Yadid
Dopaminergic mesolimbic and mesocortical systems are fundamental
in hedonia and motivation. Therefore their regulation should
be central in understanding depression treatment. This review
highlights the dopaminergic activity in relation to depressive
behavior and suggests two putative receptors as potential
targets for research and development of future antidepressants.
In this article we review data that describe the role of serotonin
in regulating dopamine release, via 5HT2C and 5HT3
receptors. This action of serotonin appears to be linked to
depressive-like behavior and to onset of behavioral effects
of antidepressants in an animal model of depression. We suggest
that drugs or strategies that decrease 5HT2C and
increase 5HT3 receptor-mediated dopamine release
in the limbic areas of the brain may provide a fast onset
of therapeutic effect. Clinical and basic research data supporting
this hypothesis are discussed.
[Back to top]
Serotonin-Dopamine Interaction as a Focus of Novel
Antidepressant Drugs
E. Esposito
Central serotonergic and dopaminergic systems play a critical
role in the regulation of normal and abnormal behavior. Recent
evidence suggests that a dysfunction of dopamine (DA) and
serotonin (5-HT) neurotransmitter systems contributes to various
pathological conditions. Among the multiple classes of 5-HT
receptors described in the central nervous system, much attention
has been devoted to the role of 5-HT2 receptor
family in the control of central dopa-minergic activity, because
of the moderate to dense localization of both transcript and
protein for 5-HT2A and 5-HT2C receptors
in the substantia nigra (SN) and ventral tegmental area (VTA),
as well as their terminal regions. Moreover, modulation of
5-HT2 receptor function by various drugs that has
been shown to influence DA function in these brain ar-eas
is thought to be important in motor activation, motivation,
and reward. Indeed, a number of electrophysiological and biochemical
data have shown that 5-HT2C receptor agonists decrease,
while 5-HT2C receptor antagonists enhance meso-corticolimbic
DA function. Recent studies have focused on the functional
interaction between the serotonergic and dopaminergic systems
to explain the mechanism of the antidepressant action of SSRIs
and 5-HT2 antagonists. In this ar-ticle, the most
relevant data regarding the role of these receptors in the
control of brain DA function are reviewed, and the importance
of this subject in the search of new antidepressant drugs
is discussed.
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Microdialysis Approach to Study Serotonin Outflow
in Mice Following Selective Serotonin Reuptake Inhibitors
and Substance P (Neurokinin 1) Receptor Antagonist Administration:
A Review
B.P. Guiard, L. Lanfumey and A.M. Gardier
Classical antidepressant drugs such as Selective Serotonin
Reuptake Inhibitors (SSRIs) display several disadvantages,
e.g., the onset of action (2 to 3 weeks) to start clinical
benefits is too long, and a significant proportion of patients
do not respond to this monotherapy. Several strategies have
been proposed to overcome these problems, notably the use
of potentiating agents, which combined with SSRIs, augment
or accelerate their established antidepressant activity. Recent
clinical trials proposed that compounds with dual action on
both central serotonin (5-HT) and noradrenaline (NA) systems
would have a faster action than SSRIs alone. Preclinical electrophysiological
and neurochemical studies demonstrated that the putative new
class of antidepressants, substance P (neurokinin 1) NK1 receptor
antagonists, en-hance brain monoaminergic neurotransmissions
by reducing the sensitivity of 5-HT1A autoreceptors in the
Dorsal Raphe Nucleus, and possibly α2
autoreceptors in the Locus Coeruleus. However, in several
clinical studies, a similar delay of therapeutic effects has
been reported with NK1 receptor antagonists and SSRIs. Recently
intracerebral in vivo microdi-alysis studies were
performed to examine the effects of genetic or pharmacological
blockade of Substance P (SP)/ NK1 neurotransmission on SSRIs-induced
increases in extracellular 5-HT levels in awake, freely moving
mice. New evidences suggest that the combination of a NK1
receptor antagonist with a SSRI should benefit to depressed
patients. This review describes our current knowledge of the
role of SP and its preferred NK1 receptors mainly in the modulation
of brain serotonergic activity.
[Back to top]
Basic Mechanisms of Augmentation of Antidepressant
Effects with Thyroid Hormone
T. Lifschytz, R. Segman, G. Shalom, B. Lerer, E. Gur,
T. Golzer and M.E. Newman
The thyroid hormone triiodothyronine (T3) has been used
both to augment and accelerate the clinical effects of antidepressants,
particularly the tricyclics. More recent work indicates that
it may have similar actions with regard to the SSRIs. Two
main mechanisms have been put forward to explain its antidepressant
actions, (a) an action at the nuclear level involving stimulation
of gene transcription, (b) an action at the cell membrane
level involving potentiation of neurotransmission. In particular,
there is considerable evidence for potentiation by T3 of the
actions of the neurotrans-mitter 5-HT or serotonin. This evidence,
which is mainly based on in vivo microdialysis studies,
is reviewed, and ev-dence based on human and animal neuroendocrine
studies considered. The effects of T3, alone and together
with the SSRI fluoxetine, on mRNA levels for the 5-HT1A
and 5-HT1B autoreceptors, which mediate serotonergic
neurotransmis-sion by feedback actions at the levels of cell
firing(somatodendritic 5-HT1A autoreceptors) and
neurotransmitter release (nerve terminal 5-HT1B
autoreceptors) were also determined. Administration of a combination
of fluoxetine and T3 in-duced reductions in the transcription
of these autoreceptors, which may explain the clinical potentiating
effects of this combination, and thus link the nuclear and
neurotransmitter hypotheses of T3 action.
[Back to top]
Preventing Type 2 Diabetes in High Risk Patients:
An Overview of Lifestyle and Pharmacological Measures
E.N. Liberopoulos, S. Tsouli, D.P. Mikhailidis and M.S.
Elisaf
Background: Type 2 diabetes mellitus
(T2DM) is a common disease that is associated with an increased
risk of vascular complications. The incidence of T2DM is also
increasing. It follows that T2DM prevention is important.
Methods: Relevant articles (review
articles, randomised studies and large cohort and case-control
studies) were identi-fied through a Medline search (up to
March 2005).
Results: The first trials on T2DM
prevention were based on lifestyle intervention. The results
of these studies were im-pressive since they demonstrated
that even a small reduction in weight could significantly
reduce the incidence of T2DM. However, the main disadvantage
of lifestyle measures is that they are difficult to achieve
and sustain. Therefore, pharmacological interventions have
also been evaluated. The results of trials using metformin,
orlistat, nateglinide, acarbose, thiazolidinediones, hormone
replacement therapy, statins or fibrates are either encouraging
or require more extensive evaluation. In addition, studies
using antihypertensive drugs (mainly angiotensin-converting
enzyme inhibitors and angiotensin II receptor antagonists)
showed that these drugs could also reduce the progression
to T2DM in high risk individuals.
Conclusions: T2DM has major quality
of life and cost implications. Therefore, more research is
needed to establish safe and cost effective ways to prevent
this modern epidemic.
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Enhancing the Site-Specific Targeting of Macromolecular
Anticancer Drug Delivery Systems
M.F. Neerman
The application of macromolecules as vehicles for anticancer
drug delivery is a burgeoning field of interest. One of the
hallmarks of using such systems, however, is that they must
be capable of site-specific drug delivery. As such, augmenting
the targeting of drug delivery systems to specified sites
is paramount. To date, a number of synthetic strategies have
been utilized to introduce targeting moieties to macromolecular
drug delivery systems to enhance specific targeting. This
scheme frequently involves the introduction of some type of
biologically recognizable marker to the delivery system. Biological
evaluations have substantiated the rationale that introducing
targeting groups can signifi-cantly increase specificity.
This concise review will attempt to encompass what strategies
have been done to increase the specificity of macromolecular
anticancer drug delivery systems along with their biological
activities.
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