A Review on Novel Strategies for Pharmacotherapy of
Depression
Manan
A Patel *, Chetan M Patel, Dipen B Patel, IS Anand and CN Patel
Shri
ABSTRACT:
Major depressive disorder is a mental disorder characterized by an
all-encompassing low mood accompanied by low self-esteem, and loss of interest
or pleasure in normally enjoyable activities. Prevalence rate of major
depression is markedly rising all over the world. Pathophysiology of depression
is mainly focus on the three major monoamine systems—serotonin (5-hydroxytryptamine,
5HT), nor epinephrine (NE), and dopamine (DA). The emerging new
tools of molecular neurobiology and functional brain imaging have
provided additional support for the involvement of these three
systems. Popular conventional drugs for pharmacotherapy of Depression are
Tricyclic anti-depressants, Monoamine oxidase inhibitors and Selective
Serotonin Re-uptake inhibitors. Major
drawbacks of these drugs include suicide tendency and discontinuation syndrome
and there is need of time to focus research at
minimising side effects. In
last two decades, many new drugs became available in market for pharmacotherapy
of depression including novel Selective Serotinin Norepinephrine re-uptake
inhibitors and still reserves bright scope in research of anti-depressant. On the other hand, a number of
alternative therapeutic strategies are now emerging, as exemplified by the
first Substance P receptor antagonist, MK-0869, and several
Corticotrophin-releasing factor antagonists now entering clinical
trials. Preclinical models predict that some of these new drugs may have a
faster onset of action and improved efficacy. It is clear to note that the next
generation of drugs will need to tackle some of the unresolved problems of
antidepressant therapy such as suicide tendency.
KEY WORDS: SSRIs, Drawbacks of antidepressants, advantages of SNRIs, Novel research in
antidepressants.
INTRODUCTION:
Major depressive disorder is a mental
disorder characterized by an all-encompassing low mood accompanied by low
self-esteem, and loss of interest or pleasure in normally enjoyable activities.1
In other words, also known as clinical depression, major depression, unipolar
depression, or unipolar disorder. The term "major depressive
disorder" was selected by the American Psychiatric Association to
designate this symptom cluster as a mood disorder in the 1980 version of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-III) classification,
and has become widely used since. The general term depression is often used to
describe the disorder. Depression is best summarized
as virtually a prototype gene-environment interaction model with
much focus on the three major monoamine systems—serotonin (5-hydroxytryptamine,
5HT), norepinephrine (NE), and dopamine (DA). The emerging new tools
of molecular neurobiology and functional brain imaging have provided
additional support for the involvement of these three systems. Now
it is evidenced that pre eminent role for central nervous system
(CNS) DA circuits exist in pathophysiology of depression.2
History of Anti-depressants:
Around the mid-1950s; various opiates and amphetamines
were commonly used as antidepressants afterwards they fell out of favor due to
their addictive nature and side effects. Among herbals, popular was extracts
from the herb
CLASSES OF ANTI DEPRESSANTS:
1.
Tricyclic Antidepressants:
Tricyclic antidepressants are the oldest class of
antidepressant drugs. Tricyclics block the reuptake of certain
neurotransmitters such as norepinephrine (noradrenaline) and serotonin. They
are used less commonly now due to the development of more selective and safer
drugs. Side effects include increased heart rate, drowsiness, dry mouth,
constipation, urinary retention, blurred vision, dizziness, confusion, and
sexual dysfunction. Toxicity occurs at approximately ten times normal dosages;
these drugs are often lethal in overdoses, as they may cause a fatal
arrhythmia. However, tricyclic antidepressants are still used because of their
effectiveness, especially in severe cases of major depression. (Table: 1)
Table 1: Past
Treatment agents for Pharmacotherapy of Depression
|
Sr. No. |
Class |
Drug GenericName |
Brand Name |
|
1. |
Tricyclic Antidepressants |
Amitriptyline |
Norpramin Sinequan Tofranil Pamelor Vivactil Surmontil |
|
Amoxapine |
|||
|
Desipramine |
|||
|
Doxepin |
|||
|
Imipramine |
|||
|
Nortriptyline |
|||
|
Protriptyline |
|||
|
Trimipramine |
|||
|
2. |
Atypical Antidepressants |
Maprotiline Trazodone Nefazodone Mirtazapine Bupropion |
|
|
|
|||
|
|
|||
|
|
|||
|
|
|||
|
|
|||
|
3. |
Monoamine Oxidase Inhibitors (MAOIs) |
Selegiline Isocarboxzaid Phenelzine Tranylcypromine |
Emsam (Skin Patch) Marplan Nardil Parnate |
|
4. |
Selective Serotonin Reuptake Inhibitors (SSRIs) |
Citalopram Escitalopram Paroxetine Paroxetine |
Celexa Lexapro Paxil Pexeva |
2.
Monoamine Oxidase Inhibitors (MAOIs):
Monoamine oxidase inhibitors are a class of powerful
antidepressant drugs prescribed for the treatment of depression. They are
particularly effective in treating atypical depression, and have also shown
efficacy in smoking cessation.
Mode of action: MAOIs act by inhibiting the activity of
monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters
and thereby increasing their availability. There are two isoforms of monoamine
oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin,
epinephrine and norepinephrine. MAO-B preferentially deaminates
phenylethylamine and trace amines. Dopamine is equally deaminated by both
types.5
Reversibility: The early MAOIs inhibited monoamine oxidase
irreversibly. When they react with monoamine oxidase, they permanently
deactivate it, and the enzyme cannot function until it has been replaced by the
body, which can take about two weeks. A few newer MAOIs, notably moclobemide,
are reversible, meaning that they are able to detach from the enzyme to
facilitate usual catabolism of the substrate. The level of inhibition in this
way is governed by the respective concentrations of the substrate and the MAOI.
Several drawbacks:
When ingested orally, MAOIs inhibit the catabolism of
dietary amines. When foods containing tyramine are consumed (so-called
"cheese syndrome"), the individual may suffer from hypertensive
crisis. If foods containing tryptophan are consumed, hyperserotonemia may
result. The amount required to cause a reaction varies greatly from individual
to individual, and depends on the degree of inhibition, which in turn depends
on dosage and selectivity.5
Withdrawal: Antidepressants including MAOIs have some
dependence producing effects, most notably a withdrawal syndrome, which may be
severe especially if MAOIs are discontinued abruptly or over-rapidly. However,
the dependence producing potential of MAOIs or antidepressants in general is
not as significant as benzodiazepines. 5
3. Selective Serotonin
re-uptake inhibitors :
Mechanism of action: Specific serotonin uptake
inhibitors increase 5-HT by inhibiting reuptake. Current theory holds that
enhanced stimulation or responsiveness of postsynaptic 5-HT1 receptors is particularly important in the action of
antidepressants.
Advantages over Past
Treatment: SSRIs had a
number of real advantages over the TCAs. It may include:
1. Easier to prescribe.
2. Better tolerated.
3. Much safer in overdose.
4. Greater efficacy in severe depression
5. In retrospect, given the high prevalence of
untreated depression in the early 1990s and the real limitations of the TCAs
(i.e., common side effects and potential lethality in overdose), were reported
as reasons of the remarkable commercial success of the SSRIs.
6.
Other
medications introduced in the 1980s and 1990s, for example, bupropion,
mirtazapine, nefazodone offered selected advantages in comparison to the SSRIs
and there was less evidence compared to SNRIs to suggest that any of these
medications were more effective for treatment of depressed outpatients.
Major Drawbacks:
Suicide tendency: It is believed that selective serotonin
reuptake inhibitors (SSRIs) and other antidepressants may increase the risk of
suicidal ideation and behaviour in children, adolescents, and adults younger
than 25 years.6,7
Evidence of Association: Establishing the causal association is
difficult because of the clear associations between severe depression and
suicide and between severe depression and the need for antidepressant therapy.
Because suicide is uncommon, it also is difficult to demonstrate the negative,
which is that antidepressants do not cause suicide. Evidence for and against an association
between antidepressant therapy and suicidal thoughts and/or behaviors in
children, adolescents, and young adults comes from randomized trials. Thus,
individual trials typically lack the power to detect a relationship between
antidepressants and suicidal ideation or behavior.
Black Box Warning: In
2004, the United States Food and Drug Administration (FDA) asked manufacturers
of a number of antidepressants to make labelling changes to include a warning
about a possible increased risk of suicidal ideation or behaviour, particularly
at the initiation of therapy or at the time of dose changes. The FDA requires
all antidepressants, including fluoxetine, to carry a black box warning stating
that antidepressants may increase the risk of suicide in persons younger than
25. After further analysis, in October 2004, the FDA directed manufacturers of
all antidepressants (including tricyclic antidepressants and monoamine oxidase
inhibitors) to include a warning stating that antidepressants may increase the
risk of suicidal ideation and behaviour in children and adolescents.8
4. Natural anti- depressants:
S-Adenosyl-Methionine, or Sam-e for short, is one of
the most popular natural antidepressants. In fact, it’s been widely recommended
by physicians in
5. Selective Serotonin
Nor-epinephrine reuptake inhibitors (SNRIs):
Mechanism of Action of SNRIs: SNRIs such as Venlafaxine and duloxetine,
referred to as dual-action antidepressants, uniquely block the reuptake of
serotonin (5HT), norepinephrine (NE), and dopamine (DA); unique because uptake
blockade depends on drug dosage. This mechanism of action contrasts with TCA
reuptake inhibition which results in the elevation of 5HT and NE but not DA.
Whereas TCAs block 5HT and NE reuptake in a relatively fixed ratio, the SNRIs
apparently block 5HT at lower doses, 5HT and NE at medium to high doses, and
5HT, NE, and DA at the highest doses.10
Drawbacks:
1. Suicide
tendency: In the last few years, some study results and case reports
suggested that taking antidepressants was linked with an increase in suicides,
attempted suicides, and thinking about suicide—especially for children, teens,
and young adults. Generally, the risk is higher in first month or so and then
appears to decrease as the body adjusts to the medication. Depressed
individuals may be more likely to attempt or commit suicide whether or not they
are taking antidepressants. Nevertheless, in 2004, the FDA required the
manufacturers of all antidepressants to include on their labels the following
safety warning: Antidepressants increase the risk of suicidal thinking and
behavior (suicidality) in children andadolescents with major depressive
disorder (MDD) and other psychiatric disorders.
2. Discontinuation syndrome: the abrupt discontinuation of an SNRI
usually leads to a discontinuation syndrome which could include states of
anxiety and further symptoms. It is therefore recommended to slowly taper down
the dose under the supervision of a professional when discontinuing SNRIs.
Discontinuation syndrome has been reported to be markedly worse for venlafaxine
when compared to other SNRIs.11 This is likely due to venlafaxine's
relatively short half-life and therefore rapid clearance upon discontinuation.
Advantages of SNRIs:
Superiority: Venlafaxine, the first SNRI, made its debut
in 1993 as a multiple dose immediate release (IR) tablet. Despite promising
evidence that Effexor offered improved efficacy over SSRIs without the toxicity
risk of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants
(TCAs), patients were not able to tolerate the high incidence of nausea. Wyeth
came to the rescue in 1997 by reformulating the drug into an extended release
capsule of microspheroids, providing a slower rate of absorption compared with
the IR tablet. This new XR formulation showed higher remission rates for major
depressive disorder (MDD) when compared to SSRIs and a tolerability profile
similar to that of SSRIs.19 Dual-action agents (SNRIs) are more effective than
SSRIs in the treatment of MDD. There is a growing amount of evidence to support
this hypothesis.12
Interest in drugs that
inhibited reuptake of both serotonin and norepinephrine was fueled in part by
the findings of the Inpatient studies conducted by the Danish University
Antidepressant Group (DUAG), in which clomipramine—the only TCA that is a
strong inhibitor of serotonin reuptake—was significantly more effective than
both citalopram and paroxetine. Several pharmaceutical companies therefore
focused on development of selective serotonin norepinephrine reuptake
inhibitors (SNRIs), with the aim of introducing antidepressants that conveyed
the efficacy advantage of clomipramine while offering a side effect profile
more comparable to an SSRI.
Drug Profile of SNRIs:
1. Duloxetine:
Trade Name:
Cymbalta 60 mg
It is effective for major depressive disorder and it is
as effective as venlafaxine in generalized anxiety disorder, it is a well
tolerated and is considered a first line treatment strategy.14
Duloxetine was approved for this indication of stress urinary incontinence in
Side effects: Nausea, somnolence, insomnia, and dizziness
are the main side effects, reported by about 10% to 20% of patients. 23 In a
trial for mild major depressive disorder (MDD), the most commonly reported
treatment-emergent adverse events among duloxetine-treated patients were nausea
(34.7%), dry mouth (22.7%), headache (20.0%) and dizziness (18.7%), and except
for headache, these were reported significantly more often than in the placebo
group.
2. Venlafaxine:
Brand Name: Effexor, Efexor
In 2007, venlafaxine was the sixth most commonly
prescribed antidepressant on the
Investigational uses: Venlafaxine as "off label" used
for the treatment of diabetic neuropathy and migraine prophylaxis.16 Due
to its action on both the serotoninergic and adrenergic systems, Venlafaxine is
also used as a treatment to reduce episodes of cataplexy, a form of muscle
weakness, in patients with the sleep disorder narcolepsy. Due to its tendency
to increase blood pressure and its modulative effects on the autonomic nervous
system, venlafaxine is often used to treat orthostatic intolerance and postural
orthostatic tachycardia syndrome.17
Mechanism of Action: Venlafaxine is a bicyclic antidepressant,
and is usually categorized as a serotonin-norepinephrine reuptake inhibitor
(SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine
reuptake inhibitor.18 It works by blocking the transporter
"reuptake" proteins for key neurotransmitters affecting mood, thereby
leaving more active neurotransmitters in the synapse.
3. Desvenlafexine:
Desvenlafaxine (Pristiq) is an
antidepressant of the serotonin-norepinephrine reuptake
inhibitor class from Wyeth.
Desvenlafaxine succinate, a serotonin-norepinephrine reuptake inhibitor (SNRI),
is the succinate salt of a major active metabolite of venlafaxine hydrochloride
known as O-desmethyl venlafaxine.
Investigational Uses: Desvenlafaxine is also under investigation
for the treatment of vasomotor symptoms associated with menopause. Speroff et
al, have reported desvenlafaxine to be an efficient non-hormonal therapy for
vasomotor symptoms in postmenopausal women.
Adverse effects: The most common adverse effects observed
during the treatment included anorexia, constipation, nausea, nervousness, and
somnolence.
Brand Name: Ixel, Savella
In January 2009 the U.S. Food and Drug Administration
(FDA) approved milnacipran (under the brand name Savella) for the
treatment of fibromyalgia, making it the third medication
approved for this purpose in the United States. 21
Mechanism of Action: Milnacipran inhibits
norepinephrine and serotonin reuptake in a 3:1 ratio, in practical use this
means a balanced (equal) action upon both transmitters. The serotonin reuptake
inhibition is likely to improve depression, while the norepinephrine reuptake
inihibition probably improves chronic pain. Milnacipran exerts no significant actions
on postynaptic H1, alpha-1, D1, D2, and muscarinic receptors, as well as on
benzodiazepine binding sites.22, 23
Side effects: Side effects include
itching, nausea, vertigo, increased anxiety, sweating, shivering, dysuria.
6. Noradrenergic and specific serotonergic
antidepressants (NaSSAs):
Noradrenergic and specific
serotonergic antidepressants are a class of psychoactive drugs used primarily
as antidepressants. They act by antagonizing various adrenergic and serotonin
receptors, of which typically consist of α1-adrenergic and/or
α2-adrenergic, and 5-HT2A, 5-HT2C, and/or 5-HT3. Unlike most conventional
antidepressants, the NaSSAs have no efficacy as serotonin reuptake inhibitors
(SRIs).
List of NaSSAs:
1.
Mianserin (Bolvidon, Norval,
Tolvon)
2.
Mirtazapine (Remeron)
3.
Setiptiline (Tecipul)
1. Mianserin:
Mianserin (Bolvidon, Norval,
Tolvon) is a psychoactive drug of the tetracyclic antidepressant (TeCA)
chemical class which is classified as a noradrenergic and specific serotonergic
antidepressant (NaSSA) and has antidepressant, anxiolytic, hypnotic,
antiemetic, orexigenic, and antihistamine effects. It was previously available
internationally, however in most markets it has been phased out in favor of its
analogue and successor mirtazapine (Remeron).
Pharmacology: Mianserin is an antagonist
at the H1, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, and
α2-adrenergic receptors, and also acts as a norepinephrine reuptake
inhibitor (NRI) via blockade of the norepinephrine transporter (NET).24
Side Effects: Common side effects of
mianserin may include dizziness, blurred vision, sedation, drowsiness or
somnolence, increased appetite or hyperphagia and subsequent weight gain, dry
mouth or xerostomia, and constipation, among others. Potentially serious
adverse reactions may include and allergic reaction, fainting or syncope,
seizures or convulsions, and white blood cell reduction or agranulocytosis.
2. Setiptiline:
Setiptiline (Tecipul), also known
as teciptiline, is a psychoactive drug of the tetracyclic antidepressant (TeCA)
chemical class. It acts as a noradrenergic and specific serotonergic
antidepressant (NaSSA), and is thought to have a very similar pharmacological
profile to those of mianserin (Bolvidon, Norval, Tolvon) and mirtazapine
(Remeron) and acting as an α2-adrenergic, 5-HT2A, 5-HT2C, and 5-HT3
receptor antagonist, among other effects.
3. Mirtazapine:
Mirtazapine (Remeron) is
tetracyclic antidepressant (TeCA) chemical classes which is used primarily as
an antidepressant.
Pharmacology: Mirtazapine is a potent
antagonist at the following receptors: H1 ,5-HT2A ,5-HT2C ,5-HT3
,α2-adrenergic. 25 Despite its classification as a NaSSA based
on its relatively weak actions at the α2-adrenergic receptor,
mirtazapine's antidepressant properties are more likely to actually be mediated
primarily by its far stronger blockade of various serotonin receptors, notably
the 5-HT2C receptor.
Side effects: Common side effects of
mirtazapine may include dizziness, blurred vision, sedation, drowsiness or
somnolence, malaise or lassitude, increased appetite or hyperphagia.
7. Norepinephrine reuptake inhibitors (NRIs):
1. Reboxetine:
Reboxetine is an antidepressant
drug used in the treatment of clinical depression, panic disorder and ADD/ADHD,
developed by Pfizer. Its mesylate (i.e.methanesulfonate) salt is sold under
tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra.
Mode of action: Unlike most antidepressants
on the market, reboxetine is a norepinephrine reuptake inhibitor (NRI); it does
not inhibit the reuptake of serotonin, therefore it can be safely combined with
an SSRI.
2. Atomoxetine:
Atomoxetine is a non-stimulant
drug approved for the treatment of attentional difficulties. It is sold in the
form of the hydrochloride salt of atomoxetine, a Norepinephrine Reuptake
Inhibitor.
Side
effects: The side effects include, dry mouth, insomnia, nausea, decreased appetite,
constipation, dizziness, sweating, dysuria, sexual problems, weight changes,
palpitations, increases in heart rate and blood pressure.26
Off-label
uses: Atomoxetine,
which inhibits the reuptake of norepinephrine, was originally explored by Eli
Lilly as a treatment for depression, but did not show a benefit to risk ratio
in trials.
Mazindol is a central nervous system stimulant.
It is a tricyclic compound and mazindol is thought to act as a reuptake inhibitor of norepinephrine.
It is marketed under the brand names Mazanor and Sanorex.
8. Selective Serotonin reuptake enhancers (
Tianeptine (Stablon, Coaxil,
Tatinol), is a selective serotonin reuptake enhancer
(SSRE) drug used
for treating Major depressive episodes (mild, moderate, or severe). Unlike
conventional tricyclic antidepressants, tianeptine
enhances the reuptake of serotonin instead of inhibiting it, opposite to the action of
SSRIs. Moreover, it enhances the extracellular concentration of dopamine
in the nucleus accumbens. 28 Tianeptine, indicated as a thymoleptic,
reduces the effects of serotonin in the limbic system and the pre-frontal
cortex, giving rise to a mood elevation, unlike the mood blunting associated
with SSRIs.
Tianeptine shows efficacy
against serious depressive episodes (major
depression), comparable to amitriptyline,
imipramine
and fluoxetine,
but with fewer side effects. It was shown to be more effective than maprotiline
in a group of patients with co-existing depression and anxiety.
NOVEL DRUGS UNDER RESEARCH AND DEVELOPMENT:
1. Substance P receptor antagonists:
Until now, the clinical rewards of
neuropeptide research have been limited compared with the monoamines. Since the
discovery of the first small molecule receptor antagonists of the substance P
(SP) preferring neurokinin 1 (NK‑1) 1990, SP has been pursued as a
therapeutic target for conditions as diverse as pain, inflammation, emesis and
depression. The localisation of SP in brain regions that coordinate stress responses
and receive convergent monoaminergic innervation (e.g. the locus coeruleus and
the amygdala) suggest that SP receptor antagonists (SPAS) might have potential
as psychotherapeutic agents. Recent
behavioural studies using an NK1 receptor knockout mouse have also
suggested that SP plays an important role in the adaptive response to stress
and emotional behaviour.
The clinical development
compound MK-0869 (Figure: 1) shows high affinity and
selectivity for the NK1 receptor, CNS penetration and good oral bioavailability
and is therefore suitable as an oral therapeutic candidate. In a six-week
randomised double-blind placebo-controlled trial in outpatients with moderate
to severe depression, the effects of the SPA MK 0869 (300 mg) were compared
with an active comparator , the SSRI paroxetine (20 mg) or placebo.29
This molecule, provide the
first clinically validated new mechanistic non-monoaminergic approach to
antidepressant therapy. MK-0869 and other SPAS offer an alternative approach to
therapy for depressed patients who respond or comply poorly to currently
available drugs. Further clinical trials to confirm and define the therapeutic
profile of SPAS are in progress.
Figure 1:
Substance P receptor antagonist: MK-0869
Where MK-0869 is coding for novel
antidepressant molecule
2.
Corticotrophin-releasing factor antagonists:
There has also been growing interest in the
role of another neuropeptide, corticotrophin-releasing factor (CRF), in
depression and anxiety disorders.30 There is evidence to suggest
that CRF is hypersecreted in depression and stress-related disorders.
Post-mortem brain tissue from depressed patients shows a marked increase in the
number of hypothalamic paraventricular neurones that express CRF.31
CRF is thought to act both as a neurohormone, stimulating the release of
adrenocorticotropic hormone (ACTH) from the pituitary (and subsequently
glucocorticoids from the adrenal gland), and a neuromodulator in other brain
regions. Two major CRF receptor subtypes (CRFRl and CRFRZ) and a functionally-related
peptide, urocortin, have been identified. CRFRl is highly expressed in the
brain, including the anterior pituitary, locus coeruleus, neocortex,
hippocampus, amygdala and cerebellum, whereas CRFRZ is more abundant in
peripheral tissues. Mice with a targeted disruption in the CRFRl locus have
been generated to elucidate the specific roles of CRF receptor-mediated
pathways. Data indicate that CRF mediates the responses to stress and anxiety
via the CRFRl receptor. Animal experiments with acute administration of the
nonpeptide CRF antagonist, CP-154,526, ( Figure :2) which has selectivity for
the CRFRl subtype produced satisfactory results till date.32 Other antagonists, including DMP696, NB130775 and NGD
98-l are now believed to be entering clinical trials.
Figure 2: Corticotrophin-releasing
factor antagonists: CP-154,526
Where MK-0869 is coding for novel antidepressant molecule
3. Modulation of
other receptors: Gama amino butyric acid and glutamate:
Gama amino butyric acid (GABA) and glutamate are the principal inhibitory
and excitatory neurotransmitters in the central nervous system, respectively.
The GABA, receptor is the site at which the anxiolytic and sedative effects of
the benzodiazepines are exerted. Other allosteric modulators of the GABA,
receptor ion channel have been investigated, including the neurosteroid
dehydroepiandrosterone (DHEA) since depressed patients are thought to have
abnormally low levels of DHEA.33
Two GABA, receptor agonists, NGD 91-2 and NS 2710, are also entering
initial clinical trials for anxiety and depression. The presynaptic group
II/III metabotropic glutamate (mGlu) agonists, like p-opiate agonists, can
suppress the 5- HTinduced glutamatergic excitatory activity in the neocortex. (figure-3)
Thus, it is possible that selective glutamate receptor agonists may be
beneficial in the treatment of anxiety-related disorders without the adverse
effects seen with benzodiazepines. The mechanism of action of antidepressants
cannot be unequivocally attributed to their acute pharmacological actions, and
their delayed onset may reflect the fact that their therapeutic effect, like
the pathogenesis of depression, is an adaptive process. Research has
demonstrated that neural plasticity and learning, which may underlie the induction
of depression by repetitive stress, involve gene transcription through
Figure 3: Gama amino butyric acid
and glutamate : DMP-696
Where MK-0869 is coding for novel antidepressant molecul Reduced levels of this neurotrophic factor could
contribute to the atrophy and decreased function of stress-vulnerable
hippocampal neurons. In contrast, chronic antidepressant treatment increased
the expression of BDNF in rat hippocampus and could thereby reverse the
stress-induced atrophy of neurons or protect these neurons from further
damage.. Chronic administration of inhibitors of phosphodiesterase (PDE, the
enzyme responsible for the metabolism of CAMP), such as rolipram or papaverine,
also increased expression of CREB mRNA in the rat hippocampus. Clinical trials
have shown that rolipram has antidepressant efficacy, however the therapeutic
potential of this drug may be limited by nausea as a major adverse effect.
Up-regulation of the cAMP system thus presents a novel model for the mechanism
of action of antidepressants and new targets for the development of therapeutic
agents.35
DISCUSSION:
A major problem with the current focus on enhancing the efficacy of SSRIs
is that this may also enhance the adverse effects. In last two decades, many
new drugs became available in market for pharmacotherapy of depression including
novel SNRIs and still reserves bright scope in research of anti-depressant.On
the other hand, a number of alternative therapeutic strategies are now
emerging, as exemplified by the first Substance P receptor antagonist, MK-0869,
and several Corticotrophin-releasing factor antagonists now entering clinical
trials.Preclinical models predict that some of these new drugs may have a
faster onset of action and improved efficacy.It is clear to note that the next
generation of drugs will need to tackle some of the unresolved problems of
antidepressant therapy such as suicide tendency.
REFERENCES:
1.
www.who.int/mental_health/management/depression/
2.
Kuhn R
.The Treatment of Depressive States with G 22355 (Imipramine Hydrochloride).
American Journal of Psychiatry (American Psychiatric Association); 115 (5):
459–464.
3. Healy D. Lines of evidence on the risks of
suicide with selective serotonin reuptake inhibitors. Psychother Psychosom
2003; 72:71.
4. Whittington CJ, Fonagy, P, et al. Selective
serotonin reuptake inhibitors in childhood depression: systematic review of
published versus unpublished data.2004; 363:1341.
5.
http://www.wisegeek.com/what-are-the-different-types-of-natural-antidepressants.htm
6. Keltner NL, and Folks DG. Psychotropic drugs. St.
Louis, MO: Mosby 2005.
7. Perahia DG, Pritchett YL,
Kajdasz DK, Bauer M, Jain R, Russell JM, Walker DJ, Spencer KA, Thase ME. A
randomized, double-blind comparison of duloxetine and venlafaxine in the
treatment of patients with major depressive disorder.". J Psychiatr Res. 2008;
42 (1): 22–34.
8. Charney DS.Monoamine dysfunction and the
pathophysiology and treatment of depression. J Clin Psychiatry 1998; 59(Suppl
14):11–14.
9. Ressler KJ, Nemeroff CB: Role of
norepinephrine in the pathophysiology of neuropsychiatric disorders. CNS Spectr.
2001; 6:663–666.
10.
Kornstein
SG, Russell JM, Spann ME, Crits-Christoph P, Ball SG.Duloxetine in the
treatment of generalized anxiety disorder". Expert Rev Neurother.2009; 9
(2): 155–165.
11.
Duloxetine:
new drug. For stress urinary incontinence: too much risk, too little
benefit". Prescrire Int 2004;14 (80): 218–20. available at:www.ncbi.nlm.nih.gov.in
12.
Perahia
DG, Kajdasz DK, Desaiah D, Haddad PM .Symptoms following abrupt discontinuation
of duloxetine treatment in patients with major depressive disorder. J Affect
Disord.2005; 89 (1-3): 207–212.
13.
Stone
MB, Jones ML .clinical review: relationship between antidepressant drugs and
suicidality in adults" (pdf). Avilable at: Http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-fda.pdf
14.
Parikh
AR,Thatcher BT, Tamano EA .Suicidal ideation associated with duloxetine use: a
case series". J clin psychopharmacolgy.2008; 28 (1): 102.
15. www.wyethpharmaceuticals.com/data/clinical
trials.httm
16.
Thundiyil
JG, Kearney TE, Olson KR .Evolving epidemiology of drug-induced seizures
reported to a Poison Control Center System". J Med Toxicol. 2007: 19
17. Yeung, PP, Entsuah, R,Manley AL .A double-blind,
placebo-controlled study of the efficacy and safety of desvenlafaxine succinate
in the treatment of major depressive disorder.J Clin Psychiatry ;2007: 68 (5):
677–688.
18. Liebowitz MR, Yeung, PP, Entsuah, R. A randomized,
double-blind, placebo-controlled trial of desvenlafaxine succinate in adult
outpatients with major depressive disorder. J Clin Psychiatry.2003 68 (11):
1663–1672.
19.
Briley
M, Prost JF, Moret C.Preclinical pharmacology of milnacipran. International
clinical psychopharmacology.1996;11 : 9–14.
20.
Puozzo
C, Panconi E, Deprez D.Pharmacology
and pharmacokinetics of milnacipran. International clinical psychopharmacology.
2002; 17 : S25–S35.
21. http://www.drugs.com/newdrugs/forest-cypress-announce-fda-approval-savella-management-fibromyalgia-1232.html
22.
Moret
C, Charveron M, Finberg JP, Couzinier JP, Briley M .Biochemical profile of
midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane
(Z) hydrochloride, a potential fourth generation antidepressant drug.
Neuropharmacology.1985 ; 24 (12): 1211.
23.
Briley
M, Prost JF, Moret C. Preclinical pharmacology of milnacipran. International
clinical psychopharmacology.1996; 11: 9–14.
24.
Leonar B, Richelson H .Synaptic
Effects of Antidepressants: Relationship to Their Therapeutic and Adverse
Effects in Buckley. Schizophrenia and Mood Disorders.The New Drug Therapies in
Clinical Practice.2002:23.
25. Boer TH, Maura G, Raiteri
M, Vos CJ, Wieringa J, Pinder RM.
Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of
mianserin, Org 3770 and its enantiomers. Neuropharmacology.1988; 27 (4):
399–408
26. Simpson
D, Plosker GL.Spotlight on atomoxetine in adults with attention-deficit
hyperactivity disorders. CNS Drugs .2004; 18 : 397–401.
27. Müller-Oerlinghausen B,
Rüther E.Clinical profile and serum concentration of
viloxazine as compared to amitriptyline. Pharmakopsychiatrie,
Neuro-Psychopharm.1979;12 (4): 321–337.
28.
Invernizzi R.Tianeptine increases the
extracellular concentrations of dopamine in the nucleus accumbens by a
serotonin-independent mechanism. Neuropharmacology.1992; 3: 211-217.
29. Kramer MS, Cutler N,
Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D,
Wyatt-Knowles E. Distinct mechanism for antidepressant activity by blockade of
central substance P receptors. Science.1998;281:1640-l645.
30. Mitchell AJ. The role
of corticotropin releasing factor in depressive illness: a critical review.
Neurosci Biobehav Rev. 1998; 22:635-651.
31. Raadsheer FC, van
Heerikhuize JJ, Lucassen PJ; Corticotropinreleasins hormone mRNA in
paraventricular nucleus of oatients with
Alxheimer’s disease or depression. Am J Psychiatri.1995; 152: 1372-1376.
32. Blanquet V, Steckler T,
Holsboer F, Wurst W. Impaired stress response and reduced anxiety in mice
lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet .1998;
19:162-163.
33. Wolkowitz OM, Reus VI,
Roberts E, Manfredi F, Chan T, Raum WJ,Ormiston S, Johnson R, Canick J,
Brizendine L, Weingartner H.Dehydroepiandrosterone (DHEA) treatment of
depression. Biol Psychiab.1997; 41:31
34. Smith MA, Makino S,
Kvetnansky R, Post RM. Stress alters the expression of brain-dirived
neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci
.1995; 15:1768-l 777.
35. Duman RS.Novel
therapeutic approaches beyond the serotonin receptor. Biol Psychiatry.1998; 44: 324-335.
Received on 31.12.2009
Accepted on 20.02.2009
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Research J. Pharmacology and
Pharmacodynamics 2(2): March –April 2010: 153-159