| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 11, Number 2 , 2005
Contents
Antidepressant Drug Design
Executive Editor: Lee E. Schechter
Editorial Pp.
143-144
Lee E. Schechter
Increasing Hippocampal Neurogenesis: A Novel Mechanism
for Antidepressant Drugs Pp. 145-155
Jessica E. Malberg and Lee E. Schechter
[Abstract]
Opportunities to Discover Genes Regulating Depression
and Antidepressant Response from Rodent Behavioral Genetics
Pp. 157-169
James J. Crowley and Irwin Lucki
[Abstract]
Animal Models of Depressive Illness: The Importance
of Chronic Drug Treatment Pp. 171-203
P.J. Mitchell and P.H. Redfern
[Abstract]
The Central Vasopressinergic System: Examining
the Opportunities for Psychiatric Drug Development Pp.
205-225
Robert H. Ring
[Abstract]
Clinical Perspectives on Antidepressant Drug Development:
A Critical Discussion Pp. 227-231
M.A. Demitrack
[Abstract]
General Articles
Hypericin - The Facts About a Controversial
Agent Pp. 233-253
A. Kubin, F. Wierrani, U. Burner, G. Alth, W. Grunberger
[Abstract]
History Repeats Itself: Pharmacodynamic Trends
in the Treatment of Anxiety Disorders Pp. 255-263
T.L. Schwartz, N. Nihalani, M. Simionescu and G. Hopkins
[Abstract]
Development of Molecular Targeted Anticancer Agents:
Successes, Failures and Future Directions Pp. 265-272
Eric X. Chen and Lillian L. Siu
[Abstract]
Advances in Therapy for Psoriasis: An Overview
of Infliximab, Etanercept, Efalizumab, Alefacept, Adalimumab,
Tazarotene, and Pimecrolimus Pp. 273-280
Ritu Saini, William D. Tutrone and Jeffrey M. Weinberg
[Abstract]
Abstracts
[Back to top]
Editorial
Lee E. Schechter
Major Depressive Disorder (MDD) is a prevalent mental
health disorder that was identified by the World Health Organization
in 2001 as the fourth leading cause of disability and premature
death in the world. It is estimated that by the year 2020
MDD would be only second to ischemic heart disease in regards
to disease burden. Although the past decade has resulted in
clear advances in our understanding of MDD, several issues
still remain regarding disease diagnosis and effective clinical
management. Certainly our understanding of the neurobiology
of the disease has made strides over the last two decades
and it is now quite clear that abnormalities in monoaminergic
neurotransmission plays a role based upon the efficacy of
drugs which modulate these neurotransmitter systems.
The field of antidepressant research and the development
of antidepressant agents has clearly progressed since the
discovery and introduction of the monoamine oxidase inhibitor
iproniazid. The serendipitous finding in the 1950s that iproniazid
was an effective antidepressant ignited more work focusing
on this mechanism of action and ultimately led to the hypotheses
that defects in monoaminergic neurotransmission underlie depressive
symptoms. Further progress in the field was advanced as tricyclic
antidepressants, such as imipramine, and other MAOIs including
phenelzine and pargyline were developed. However, the incidence
of side effects associated with these compounds has limited
their usefulness in clinical practice. The tricyclic antidepressants
have been compromised by anticholinergic and antihistaminergic
side effects including cardiotoxicity. MAOIs are associated
with a serious food interaction such that foods containing
tyramine could induce a hypertensive crisis in patients. The
discovery that MAOIs exist in two major forms (MAO-A and -B),
which can be distinguished by substrate affinities for norepinephrine
and 5-HT (A form) or dopamine (B form), has led to the development
of selective MAOIs for each of these forms, including compounds
such as moclobemide, designated as a reversible inhibitor
of MAO-A. While in fact moclobemide has shown efficacy comparable
to the SSRIs and is well tolerated, the potential for the
wellknown food interaction could still occur despite a larger
margin of safety.
Indeed based upon investigations in the 1960s by Carlsson
and Lindqvist it was determined that blockade of the reuptake
site of serotonergic neurons played a role in the mechanism
of action of the tricyclics such as imipramine. Subsequently
rational drug design focused upon the development of agents
with similar properties and a new era in neuropsychopharmacology
was born as the SSRIs and SNRIs were developed. The development
of the third generation of antidepressants represented by
the selective serotonin reuptake inhibitors (SSRIs) such as
fluoxetine, sertraline, citalopram and paroxetine was a major
advance in antidepressant drug therapy in the late 1980s.
During the last decade, the introduction of the dual-acting
serotonin norepinephrine reuptake inhibitor (SNRI), venlafaxine
has resulted in further treatment advances with improved efficacy,
superior remission rates over SSRIs as well as the ability
to treat the painful syndromes associated with depression.
More recently duloxetine has entered the market as another
SNRI. Despite the advantages of these therapeutic agents over
the older generation compounds in terms of efficacy and side
effect profiles it is clear that we still have not yet arrived
at the most effective side-effect free therapies for the majority
of patients. Notably issues regarding onset of action, efficacy
rates, treatment resistant patients and side effects (sexual
dysfunction and gastrointestinal symptoms) are clearly areas
for further refinement and improvement in therapies.
The therapeutic effects of SSRI or SNRI antidepressants is
believed to result from an enhancement of monoaminergic neurotransmission
resulting from long-term adaptive changes in serotonergic
and/or adrenergic receptors subtypes and perhaps other neuronal
or signal transduction systems. It seems clear that the role
of the transporter as mediating the initial step of the cascade
of molecular events that ultimately leads to antidepressant
action must be elucidated to a much greater extent than is
currently the case. Indeed the mechanism of action for known
antidepressants may involve significant functional interactions
with other neurotransmitter and neuropeptide systems, and
recent data suggests trophic factors which control neurogenesis
in the brain. In the area of peptide research the development
of novel therapies such as NK1 antagonists and CRF1 receptor
antagonists has received much attention. Notably, a NK1 antagonist
being developed by Merck was recently discontinued from Phase
III clinical trials. The reason for the discontinuation of
the NK1 antagonist is not known and it will be important to
determine if this is a failure of the mechanism or a result
of a structure-based issue. Interestingly, the vasopressinergic
system may be a fruitful area of investigation based upon
recent compelling data in depression and anxiety models. Coupled
to further understanding the molecular and biochemical events
associated with antidepressant therapy, new approaches are
being investigated in terms of behavioral models incorporating
genetic approaches and developing models which may predict
onset and other efficacy parameters particularly in terms
of novel mechanisms of drug action. Taken together, we not
only need to understand the molecular mechanisms and processes
of 5-HT and NE transporter function but also the nature and
extent of transporter function interactions with other systems.
Other areas of drug development suggest that compounds with
greater selectivity for 5-HT receptor subtypes may be even
safer, more rapid in their onset and more broadly effective
than those currently available. At the present time, it would
not appear that 5-HT1A-mediated effects are alone
sufficient to confer robust antidepressant activities; however,
clinical studies with 5-HT2C agonists or with combination
subtype-selective compounds are eagerly anticipated. One of
the most promising recent developments which is aimed at improving
onset of action and additionally efficacy in treatment-resistant
patients has been the co-administration of 5-HT1A receptor
antagonists with SSRI agents. Preclinical investigations studying
this combination have demonstrated acute increases in serotonergic
neurotransmission using both neurochemical and electrophysiological
indices supporting the rationale behind the concept. Although
this strategy has been tested in the clinical setting by co-administering
pindolol, a β-adrenergic antagonist possessing 5-HT1A
antagonist properties, further clinical studies using selective
5-HT1A receptor antagonists or single molecules combining
SSRI and 5-HT1A antagonist properties will fully validate
this therapeutic approach in the future.
As alluded to above, our understanding of depression has
progressed and new avenues for investigation are in progess.
The design of new antidepressant medications is clearly a
challenging area that is currently investigating multiple
new targets and combination strategies. The question and challenge
to investigators is the development of the next generation
of drugs with improvements in efficacy and side effect profiles.
As our understanding of depression and the subtypes of the
disease are better understood through clinical studies and
pharmacogenomics, and as our approaches to new drug design
benefit from advances in preclinical research including our
understanding of established and new animal models, further
mechanisms for antidepressant drug action will evolve leading
to novel therapeutic strategies. The goal of this issue of
Current Pharmaceutical Design is to review current advances
and aspects of this challenging area of drug development from
the preclinical to clinical arena. I trust this issue will
be of great interest and reveal the advances as well as complexities
associated in antidepressant drug design and development.
Lee E. Schechter
Therapeutic Area Head
Depression and Anxiety Research
Neuroscience Discovery
Wyeth Research
CN8000
Princeton, NJ
USA
[Back to top]
Increasing Hippocampal Neurogenesis: A Novel Mechanism
for Antidepressant Drugs
Jessica E. Malberg and Lee E. Schechter
The birth of new neurons, or neurogenesis, in the hippocampal
formation has been demonstrated throughout the lifetime of
multiple species including humans. A major finding in the
field of depression is that treatment with antidepressant
drugs increases hippocampal neurogenesis. This review presents
a current summary of this field of study and presents the
hypothesis that increasing adult hippocampal neurogenesis
may be a new drug target or mechanism for future antidepressant
drugs. It has been demonstrated that multiple classes of antidepressant
drugs increase hippocampal cell proliferation and neurogenesis
in a chronic and not acute time course, which corresponds
to the therapeutic time course necessary for effects. Conversely,
animal models of depression or stress paradigms decrease cell
proliferation. Clinically, there is evidence of reduced hippocampal
volume in patients with major depressive disorder or other
affective disorders. Taken together, this data indicates that
reduced hippocampal cell number may be involved in the pathophysiology
of depression and reversal of this may be one way the antidepressant
drugs exert their effects. We hypothesize that the next generation
of antidepressant drugs will, in addition to their effects
on known transmitter or second messenger systems, involve
either direct or indirect targeting of neurogenic factors.
In addition, the ability of novel compounds to be tested for
the neurogenic potential may become an additional way to evaluate
a compound for putative antidepressant effects.
[Back to top]
Opportunities to Discover Genes Regulating Depression
and Antidepressant Response from Rodent Behavioral Genetics
James J. Crowley and Irwin Lucki
Over the past several years, research has indicated that
an individual’s genetic makeup strongly influences not
only their likelihood of developing depression, but also whether
or not they will respond well to a particular antidepressant
treatment. Identifying those genes regulating susceptibility
to depression will increase our understanding of disease pathophysiology
and direct the development of treatments that correct underlying
neurobiological pathology related to stress-related psychiatric
illnesses. Pharmacologically, the identification of genes
regulating treatment response can lead to the design of novel
pharmacological treatments and allow for more individualized,
rational and successful drug treatments. Unfortunately, complex
environmental and genetic mechanisms at play in depression
and drug response make the discovery of susceptibility genes
in humans quite difficult. Animal models may provide a more
desirable system in which to discover susceptibility genes
because environmental factors and tests can be regulated and
more informative genetic methods can be used. Furthermore,
a unique genetic opportunity exists with animal models of
depression and antidepressant response because several rodent
strains have been identified, or selectively bred, that display
exaggerated depressive phenotypes on stress-related behavioral
tests or divergent responses to antidepressant drugs. This
paper reviews several of these rodent strains and illustrates
the genetic strategies available to discover the long-sought
susceptibility genes regulating these phenotypes.
[Back to top]
Animal Models of Depressive Illness: The Importance of Chronic
Drug Treatment
P.J. Mitchell and P.H. Redfern
A wide diversity of animal models has been used to examine
antidepressant activity. These range from relatively simple
models sensitive to acute treatment, to highly sophisticated
models that reputedly model some aspect of depressive illness
and which yield a positive response to prolonged, chronic,
drug treatment. In recent years antidepressant drug research
has focused on the search for antidepressant therapy that
has a more rapid onset of action. To be relevant, therefore,
animal models must measure the time course of drug action.
This review examines the claims of animal models to be sensitive
to chronic drug treatment and considers their relevance. First,
the review addresses the criteria necessary to examine the
validity of animal models of depressive illness. Second, those
animal models sensitive to chronic antidepressant treatment
are reviewed with respect to their validity as animal models
of either depressive illness and/or antidepressant activity.
In particular, the development and utility of two ‘ethologically-relevant’
animal models, the resident-intruder and social hierarchy
paradigms, are described in detail. These models of rodent
social and agonistic behaviour demonstrate that acute and
chronic treatment with antidepressant drugs (regardless of
their acute pharmacological activity) induce diametrically
opposite changes in rodent agonistic behaviour. It is argued
that the common ability of chronic treatment to increase rodent
aggression (which in turn results in increased hierarchical
status in closed social groups) most likely reflects the increased
assertiveness and associated externalization of emotions expressed
during recovery from depressive illness. Finally, findings
that relate observed behavioural changes to underlying neurochemical
changes are briefly reviewed.
[Back to top]
The Central Vasopressinergic System: Examining the Opportunities
for Psychiatric Drug Development
Robert H. Ring
Arginine vasopressin (AVP) is a cyclic nonapeptide synthesized
exclusively by neurosecretory cells of the central nervous
system (CNS). Two functionally distinct vasopressinergic systems
can be defined based on differences in the sites of action
and release of AVP. The peripheral vasopressinergic system
encompasses the sites of action for AVP released into peripheral
circulation (e.g. vascular smooth muscle, liver, kidney) from
nerve terminals in the posterior pituitary. Peripherally circulating
AVP is responsible for the classic endocrine functions ascribed
to this neurohormone (e.g. vasoconstriction, glycogen metabolism,
antidiuresis). The central vasopressinergic system, on the
other hand, includes the sites of AVP synthesis and release
within the CNS, where AVP acts as a neuromodulator/neurotransmitter
regulating an array of CNS-mediated functions (e.g. learning
and memory, neuroendocrine reactivity, social behaviors, circadian
rhythmicity, thermoregulation, and autonomic function). Historically,
pharmaceutical interest has focused on drug development efforts
that sought to exploit the peripheral effects of AVP. Evidence,
however, from clinical studies and animal models of CNS disorders
has directly implicated disturbances in vasopressinergic activity
in the pathophysiology of a number of human psychiatric disorders
(mood, anxiety, and cognitive disorders). This review will
examine the available evidence of central vasopressinergic
system involvement in psychiatric disorders, and the potential
opportunities for development of novel psychopharmaceuticals
around this system will be discussed. Specific lines of evidence
will be presented which rationalize each AVP receptor subtype
(V1R or V1a, V2R, V3R or V1b) as a molecular target for particular
psychiatric indications.
[Back to top]
Clinical Perspectives on Antidepressant Drug Development:
A Critical Discussion
M.A. Demitrack
Improving our knowledge of the development, course and treatment
of major depression is among the most pressing public health
concerns in medicine. It is therefore satisfying to observe
that critical advances have been made in our fundamental understanding
of this illness and related conditions in the past several
years. Among the areas of major change have been advances
in nosology and disease classification, an improved understanding
of risk factors for the development of major depression, advances
in the standards of clinical practice, enhanced societal acceptance
of patients with the disease and their treatment, and a substantial
increase in our understanding of the underlying neurobiology
of this common, disabling, and potentially lethal illness.
It is sobering, in contrast, to observe that we still use
methods of clinical study to explore new treatments with this
condition that employ study designs and measurement tools
which have changed very little over the past three decades.
In this selective review, several key areas of interest relevant
to the clinical development of antidepressants are examined.
These areas point to some suggested topics for attention in
the future.
[Back to top]
Hypericin -The Facts About a Controversial Agent
A. Kubin, F. Wierrani, U. Burner, G. Alth, W.
Grunberger
Hypericin is a naturally occurring substance found in the
common St. Johns Wort (Hypericum species) and can
also be synthesized from the anthraquinone derivative emodin.
As the main component of Hypericum perforatum, it
has traditionally been used throughout the history of folk
medicine. In the last three decades, hypericin has also become
the subject of intensive biochemical research and is proving
to be a multifunctional agent in drug and medicinal applications.
Recent studies report antidepressive, antineoplastic, antitumor
and antiviral (human immunodeficiency and hepatitis C virus)
activities of hypericin; intriguing information even if confirmation
of data is incomplete and mechanisms of these activities still
remain largely unexplained. In other contemporary studies,
screening hypericin for inhibitory effects on various pharmaceutically
important enzymes such as MAO (monoaminoxidase), PKC (protein
kinase C), dopamine-betahydroxylase, reverse transcriptase,
telomerase and CYP (cytochrome P450), has yielded results
supporting therapeutic potential. Research of hypericin and
its effect on GABA-activated (gamma amino butyric acid) currents
and NMDA (Nmethyl- D-aspartat) receptors also indicate the
therapeutic potential of this substance whereby new insights
in stroke research (apoplexy) are expected. Also in the relatively
newly established fields of medical photochemistry and photobiology,
intensive research reveals hypericin to be a promizing novel
therapeutic and diagnostic agent in treatment and detection
of cancer (photodynamic activation of free radical production).
Hypericin is not new to the research community, but it is
achieving a new and promizing status as an effective agent
in medical diagnostic and therapeutic applications. New, although
controversial data, over the recent years dictate further
research, re-evaluation and discussion of this substance.
Our up-to-date summary of hypericin, its activities and potentials,
is aimed to contribute to this process.
[Back to top]
History Repeats Itself: Pharmacodynamic Trends in the Treatment
of Anxiety Disorders
T.L. Schwartz, N. Nihalani, M. Simionescu and
G. Hopkins
The original treatment indicated for those suffering from
neurotic anxiety was to employ psychotherapy to facilitate
changes in behavior and coping with stressful events. A spectrum
of somatic treatments “from cathartics and emetics to
opium and “strengthening tonics”, from atropine
and digitalis to potassium bromide and chloral hydrate, from
barbiturates to benzodiazepines”, to serotonergics,
came to be used as well [1]. The Food and Drug Administration
originally approved many gamma-aminobutyric acid (GABA) facilitating
drugs since the 1960s for anxiety treatment. The 1980s evidenced
the approval of a few serotonergic treatments that cornered
the prescribing market and the front line of most treatment
protocols. More recently, GABAergic drugs are making a return
in the treatment of anxiety disorders. The following paper
details the pharmacodynamic history of treating anxiety and
also updates the reader as to the newer GABA-based approaches
mentioned above.
[Back to top]
Development of Molecular Targeted Anticancer Agents: Successes,
Failures and Future Directions
Eric X. Chen and Lillian L. Siu
Recent advances in molecular biology have identified numerous
steps and proteins involved in malignant transformation as
targets of anticancer therapy. Many molecular targeted agents
are now undergoing clinical development. Successful developments
of trastuzumab in treating breast cancer, imatinib in chronic
myeloid leukemia (CML) and gastrointestinal stromal tumors
(GISTs), and bevacizumab in colorectal cancer, have validated
the concept of molecular targeting and raised expectations
of patients and oncologists alike. Despite these successes,
many agents, notably matrix metalloproteinase inhibitors (MMPIs),
have failed in their development. In this review, we will
address several issues related to tumor biology and clinical
trial design that might have contributed to these successes
and failures, and discuss strategies to best optimize the
development of these novel agents.
[Back to top]
Advances in Therapy for Psoriasis: An Overview of
Infliximab, Etanercept, Efalizumab, Alefacept, Adalimumab,
Tazarotene, and Pimecrolimus
Ritu Saini, William D. Tutrone and Jeffrey M.
Weinberg
Psoriasis is a chronic skin disorder that affects approximately
2% of the US and European population. Over the last several
years, one of the major focuses in psoriasis research has
been the development of biologic therapies for this disease.
The aim of these therapies is to provide selective, immunologically
directed intervention with fewer side effects than traditional
therapies. The goal of this article is to review the progress
of the biologic agents which are available, or under investigation
for clinical use: infliximab, etanercept, efalizumab, alefacept,
and adalimumab. In addition, two other investigational therapies,
oral tazarotene and oral pimecrolimus will be discussed. Clinical
data for these agents, including the most recent phase II
and/or III study results, will be discussed, as well as the
most recent safety data.
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