Note: Descriptions are shown in the official language in which they were submitted.
CA 02591315 2007-06-12
METHOD FOR TREATMENT OF DEPRESSION AND
DEPRESSIVE MOOD DISORDERS
BACKGROUND
a. Field of the Invention
The present invention relates generally to the methods for the treatment of
depression and other depressive mood disorders, and, more particularly, to
methods for
treatment of depression and depressive mood disorders by administration of
compositions
that serve to increase the metabolism and/or turnover of serotonin.
b. Related Art
Major depression is an affective disorder (mood disorder). Common symptoms
include: persistent sadness; feelings of hopelessness or pessimism; feelings
of guilt,
worthlessness, helplessness; loss of interest in hobbies and activities that
once gave
pleasure; decreased energy; memory deficits and difficulty in making decisions
and
concentrating; insomnia, early morning wakening, or oversleeping; appetite
loss and/or
weight loss or overeating and weight gain; suicide ideations or attempts,
thoughts of death;
physical ailments such as headaches, chronic pain or digestive problems that
do not
respond to treatment. These symptoms can range from mild to severe, but
persist for two
weeks or more and often interfere with a person's daily functioning.
According to the National Institute of Mental Health, about 18 million
Americans
are afflicted with major depression annually. It has been estimated to be the
second
leading cause of disability, surpassed only by heart disease. Depression is
about twice as
prevalent in women than men and its occurrence is about two to three times
more common
in first degree relatives of depressed persons.
Substance abuse such as alcohol is common in persons with depression. It is
believed that substance abuse may be a form of self-medication in a person
with
CA 02591315 2007-06-12
2
depression. Alcohol dependence has been shown to follow the onset of
depression by an
average of 4.7 years, indicating that substance abuse such as the use of
alcohol is a pattern
of self-medication in depressive disorders (Abraham & Fava (1999). Compr.
Psychiatry
40(1): 44-50).
The causes of depression have not been conclusively identified, but it has
heretofore generally been believed that depression is a result of inadequate
levels of the
neurotransmitters, serotonin and norepinephrine, with most emphasis on the
former. Prior
efforts at treatment of depression have thus concentrated on increasing the
levels of
serotonin and/or norepinephrine: Past and current antidepressant treatments
have consisted
of primarily monoamine oxidase inhibitors, tricyclic antidepressants, and
serotonin
reuptake inhibitors. All of these treatments have been believed to function by
increasing
the amount of serotonin in nerve synapses (e.g., Sigma-Aldrich, 2003).
The first antidepressant therapies were monoamine oxidase inhibitors (MAO
inhibitors) such as iproniazid. Monoamine oxidase has two subtypes, A and B.
Monoamine oxidase A (MAO-A) metabolizes both norepinephrine and serotonin.
Thus, it
has been believed that the antidepressant effect of MAO inhibitors is the
result of increased
levels of serotonin and norepinephrine due to the MAO inhibitors blocking the
breakdown
of these neurotransmitters. Despite the proven efficacy of the MAO inhibitors
as
antidepressants, their use today has become very limited due to the serious
side effects
associated with MAO inhibitors. One of the side effects is hepatoxicity: MAO
is a very
important amine-oxidizing enzyme in the liver and the brain, and the
inactivation of MAO
interferes in the breakdown of tyramine (tyramine is a common amine in food
and some
beverages). MAO inhibitors can consequently cause excessive amounts of
tyramine to
accumulate in the brain, which can result in a hypertensive crisis or death.
Most of the
older MAO inhibitors were irreversible non-selective inhibitors meaning that
they
inhibited both MAO-A and MAO-B and predominantly inhibited the MAO-B. Today
there are several reversible selectively specific MAO-A inhibitors being
studied or in use
outside of the United States: Because of their reversibility they have a short
duration of
action, and thus are somewhat less apt to result in the inactivation of liver
metabolism and
the accumulation of tyramine.
CA 02591315 2007-06-12
3
Another class of antidepressant is tricyclic antidepressants, such as
imipramine.
Tricyclic antidepressants inhibit the reuptake of norepinephrine and serotonin
by blocking
the reuptake transporters, resulting in increased levels of these
neurotransmitters in the
nerve synapses (synaptic clefts). Because of the increased levels of the
norepinephrine in
the nerve synapses excessive cardiac stimulation can result. These cardiac
arrhythmias can
be difficult to treat and be potentially life threatening. These side effects
prompted the
development of selective serotonin reuptake inhibitors (SSRIs), which are the
most
commonly used antidepressants today. Although the SSRIs do not result in
increased
concentrations of norepinephrine and therefore avoid causing cardiac
arrhythmias, the
elevation in the serotonin in the nerve synapses can cause agitation,
restlessness,
gastrointestinal distress and sexual side effects all of which are common
symptoms of
depression (Sigma-Aldrich, 2003).
The clinical success of SSRIs in treating depression has been interpreted as
supporting the prevalent hypothesis that the etiology of depression is a
serotonin
deficiency. However, it is not clear as to how the SSRIs, tricyclic
antidepressants, or
MAO inhibitors relieve depression since there is a lag of several weeks before
any mood-
elevating effects are noticed after these treatments are started, despite the
rapid increase in
the levels of serotonin in the nerve synapses. Furthermore, the elevated
concentrations of
the serotonin in the nerve synapses have been shown to cause symptoms common
in
depression (Sigma-Aldrich, 2003). Also, the administration of serotonin or its
precursors
was markedly less effective or not effective at all when compared to the MAO
inhibitors,
tricyclic antidepressants, or the SSRIs in depressed persons (Beckmann and
Kasper (1983),
Fortschr. Neurol. Psychiatr. 511(5): 176-82; Nolen et al, (1985), Br. J.
Psychiatry 147.16-
22). So the question arises, if depression is due to the deficiency of
serotonin, then why
isn't the administration of serotonin or its precursors L-tryptophan or 5-
Hydroxytryptophan
more or at least equally effective as these antidepressant treatments? And if
depression is
due to the deficiency of serotonin, then why does it take several weeks before
any benefit
may be seen from these antidepressant therapies, even though increase the
concentration of
serotonin in the nerve synapses almost immediately upon administration? As
will be
described below, the present invention is founded on a new hypothesis that not
only
CA 02591315 2007-06-12
4
resolves these issues but also provides a basis for an improved treatment for
depression
and other depressive mood disorders.
Accordingly, there exists a need for a method for treatment of depression and
other
depressive mood disorders, that approaches the root cause of the disorder in a
more direct
manner than prior art treatments and therefore provides treatment with a
greater degree of
effectiveness. Furthermore, there exists a need for such a treatment that
produces clinical
benefits more rapidly than prior art treatments and without a significant lag
period between
initiation of the treatment and significant mood-elevating results. Still
further, there exists
a need for such a method that is substantially free of the many negative side
effects
associated with the prior art treatments. Still further, there exists a need
for such a method
that is easy to implement and can be made available on a widespread basis to
the many
sufferers of depression and other depressive mood disorders.
CA 02591315 2007-06-12
5 SUMMARY OF THE INVENTION
The present invention has solved the problems cited above, and is a method for
treatment of depression and other depressive mood disorders, comprising,
broadly,
administering to a patient an effective amount of a compound that increases
the catalytic
activity of MAO-A, so as to increase synaptic metabolism and/or turnover of
serotonin.
The increased MAO-A activity ensures effective synaptic metabolism of
serotonin to the 5-
HIAL metabolite that binds to the receptor on the post-synaptic neuron, as
opposed to
seeking to inhibit metabolism of the serotonin as in prior treatments. The MAO-
A agonist
may comprise reserpine or a reserpine analogue.
The step of administering the compound for increasing MAO-A activity may
comprise administering resperine by transdermal application, preferably at a
dosage
significantly less than about 0.03 mg/day. The resperine may be administered
transdermally at a dosage in the range from about 0.002 mg/day to about 0.02
mg/day;
most preferably, it is administered transdermally at a dosage in the range
from about 0.006
mg/day to about 0.01 mg/day.
The method may further comprise the step of combining the operative compound
with a transdermal cream for the transdermal application. The method may
further
comprise administering a caffeine compound to the patient so as to compensate
for an
antihypertensive effect of the preferred reserpine. The reserpine and the
caffeine
compound may be combined in the transdermal cream, so that they are
administered to the
patient simultaneously.
The dosage is selected such that the operative compound is administered in an
amount that is sufficient to ensure synaptic metabolism of serotonin to 5-HIAL
at a level
that prevents development of excess concentrations of serotonin in the
synaptic cleft, but
that is insufficient to deplete serotonin at a rate that results in inadequate
release of
serotonin into the synaptic cleft.
These and other features are advantages of the present invention will be more
fully
understood from a reading of the following detailed description with reference
to the
accompanying drawings.
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6
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a flow diagram showing the phases in serotonin metabolism in the
nerve
synapse, producing the 5-HIAL active metabolite and the 5-HIAA end metabolite;
FIG. 2 is a simplified view of a nerve synapse, illustrating the theory on
which the
treatment of the present invention is based, i.e., that the receptors of the
post-synaptic
neuron are activated by the 5-HIAL metabolite of serotonin, rather than by the
serotonin
itself as has been believed in conventional theories;
FIGS. 3A-3B are simplified views of a nerve synapse, similar to FIG. 2,
illustrating
the mechanism of conventional MAO inhibitors, as hypothesized by the inventor
herein
pursuant to the theory on which the present invention is based; and
FIGS. 4A-4B are simplified views of a nerve synapse, similar to FIGS. 3A-3B,
illustrating the mechanism of conventional selective serotonin reuptake
inhibitors (SSRIs),
as hypothesized by the inventor herein pursuant to the theory on which the
present
invention is based.
CA 02591315 2007-06-12
7
DETAILED DESCRIPTION
As will be described in greater detail below, the present invention is not
postulated
on the conventional theory that depression is due to deficient levels of
serotonin, but rather
on the belief that there is in fact adequate serotonin but insufficient
metabolism of the
serotonin into the active metabolite 5-Hydroxyindole acetaldehyde (5-HIAL).
The present
invention consequently employs compounds that act to increase the catalytic
activity of
MAO-A agonists in order to stimulate synaptic metabolism of serotonin to 5-
HIAL. This
approach runs contrary to the current antidepressant treatments as discussed
above,
because a compound that increases MAO-A activity has the effect of decreasing
the levels
of serotonin in the nerve synapses, whereas the conventional treatments are
aimed at
increasing serotonin levels.
a. Theoretical Basis
Serotonin is a neurotransmitter. During neurotransmission, serotonin is
released
from the pre-synaptic neuron into the synapse. It has been heretofore believed
that
serotonin then travels across the synapse gap and attaches to a specific
receptor on the
post-synaptic neuron and the nerve transmission is conducted. The present
invention is
based on an alternative hypothesis, i.e., that it is not the serotonin that
activates the post-
synaptic receptor, but that instead it is the active metabolite 5-
Hydroxyindole
acetaldehyde, which is produced within the synapse from the metabolism of
serotonin by
MAO-A.
As is shown in FIG. 1, serotonin is metabolized by MAO-A into 5-Hydroxyindole
acetaldehyde (5-HIAL), which in turn is rapidly metabolized by aldehyde
dehydrogenase
into 5-Hydroxyindoleacetic acid (5-HIAA), the latter being the major serotonin
metabolite
that is excreted in the urine. 5-HIAL has been shown to be a physiologically
active
metabolite, and can activate Long-Term Depression of the cerebellar Purkinje
neurons and
neurons in the prefrontal cortex (Palmer et al (1986) Alcohol Clin. Exp. Res.
10:682-685).
Long-Term Depression of the cerebellar Purkinje neurons and the prefrontal
cortex is
essential in learning and memory (Ito (1986), Neurosci. Res. 3:531-539). If
the cerebellar
CA 02591315 2007-06-12
8
Long-Term Depression is blocked, the ability to adaptively modify the
vestibuloocular
reflex is impaired (van Alphen & De Zeeuw (2002), Eur. J. Neurosci 16(3):486-
490).
Dysregulation of the vestibuloocular system has been correlated with
depression, as well as
impulsive and autistic personality types (Kornilova et al (1999), Hum.
Physiol. 25(5):549-
54).
The hypothalamus has serotonin accumulating neurons, capacity to uptake
5-Hydroxytryptophan (5-HTP, a precursor of serotonin), with the ability to
decarboxylate
5-HTP into serotonin (5-1-IT), and marked activity of MAO-A to metabolize
serotonin into
its metabolites 5-HIAL and 5-HIAA (Sakumoto et al (1984), Brain Res. Bull.
12(6)A:721-
33). The hypothalamus is involved in cognitive functions; thyroid function;
adrenal cortex
function that regulates blood pressure, water balance, cortisol production,
steroid hormone
production; maintenance of the waking state; appetite regulation; sense of
well being; body
temperature regulation. Many of the symptoms associated with depression can
perhaps be
correlated to a hypothalamic dysregulation. The activity of the hypothalamic-
pituitary-
adrenocortical (HPA) axis is often high in depressive disorders. Depressed
patients with
high HPA activity tend to have impaired MAO-A metabolism of serotonin and
norepinephrine resulting in low levels of the active metabolites (Stokes et al
(1987), Am. J.
Psychiatry 144(7):868-72.
In view of this evidence, it is believed that the post-synaptic receptor may
in fact be
activated by the serotonin metabolite 5-HIAL, following the metabolic pathway
shown in
FIG, 2. Immediately following receptor activation the 5-HIAL is metabolized
into 5-
HIAA, and which ultimately is excreted in the urine.
By way of verifying this theory, it will be noted that activity of the MAO-A
and the
5-HIAL in the serotonin metabolic pathway can be ascertained by measuring the
amount of
5-HIAA produced, since the 5-HIAA end metabolite can be easily measured in the
cerebral
spinal fluid (CSF) or urine of patients. Existing research has shown that the
5-HIAA levels
in the CSF of patients with major depression are low, tending to confirm
inadequate
serotonin metabolism. Furthermore, research by Mann and Malone in 1997
(Biological
Psychiatry 41(2):162-171) revealed that the CSF 5-HIAA was significantly lower
in
depressed patients involved in high-lethality suicide attempts than in the
depressed patients
having a history of low-lethality suicide attempts. Numerous research studies,
conducted
CA 02591315 2007-06-12
9
in various countries, have yielded similar findings that self-destructive
behaviors are
associated with low levels of 5-HIAA in the CSF (e.g., Brown & Lirmoila
(1990), Journal
of Clinical Psychology 51:Supplement 31-41; van Praag (1986) Suicide Life
Threat
Behavior 16(2):103-132). The prevalent belief, however, has been that the low
levels of
the serotonin metabolite 5-HIAA observed in depressed patients are due to
inadequate
levels of serotonin in the nerve synapse; by contrast, in the present
invention it is
hypothesized that these low levels of 5-HIAA are not due to inadequate levels
of serotonin
itself, but rather to inadequate metabolism of the serotonin.
The effect of daidzin to suppress ethanol intake in ethanol-preferring
laboratory
hamsters further supports the instant theory, that deficiency of the 5-HIAL
active
metabolite is a cause of depression and precipitates substance abuse. Daidzin
inhibits
aldehyde dehydrogenase, which is the enzyme that metabolizes 5-HIAL to 5-HIAA.
Daidzin analogues that inhibit aldehyde dehydrogenase, but not the compound
that
increases MAO-A activity, have demonstrated a potent antidipsotropic effect,
whereas
daidzin analogues that potently inhibited the compound that increases MAO-A
activity
produced no antidipsotropic effect (Rooke et al (2000), Lancet Journal
1(8385):1048-
1049). Furthermore, it has been shown that alcohol consumption inhibits
aldehyde
dehydrogenase, resulting in increased concentrations of 5-HIAL (Jenkins et al
(1984),
Lancet 1(8385): 1048-1049). This would appear to explain the pattern of self-
medication
via alcohol abuse that is commonly observed in patients having depressive
disorders.
Research has also shown that a genetic deficiency of the compound that
increases
MAO-A activity induces major alterations in mood and behavior in animals and
humans.
Knockout mice lacking the compound that increases MAO-A activity were found to
have
high levels of extracellular serotonin and, conversely, 40% lower spontaneous
firing of the
serotonergic neurons in the dorsal raphe nucleus (Evrard et al (2002), Eur. J.
of Neurosci.
15(5):841-851). The dorsal raphe nucleus is a major area of the brain affected
in
depressive disorders. This research supports the present hypothesis that
serotonin is not
the activator of the receptor on the post-synaptic serotonergic neuron, but
rather that the
serotonin metabolite 5-HIAL is the activator of the post-synaptic receptor,
resulting in the
firing of the serotonergic neurons such as in the dorsal raphe nucleus.
CA 02591315 2007-06-12
5
Accordingly, referring again to FIG. 2, the theory on which the present
invention is
founded may be stated as follows: During neurotransmission, serotonin is
released into the
synaptic cleft from storage vesicles present in the pre-synaptic neuron. The
serotonin is
then metabolized in the synaptic cleft by MAO-A, into the active metabolite 5-
HIAL. The
5-HIAL binds to the receptor on the post-synaptic neuron, thereby transferring
the signal.
10 The 5-
HIAL is then rapidly metabolized by aldehyde dehydrogenase into 5-HIAA, which
is eventually excreted in the urine.
Assuming this is correct, then depression and other mood disorders may
properly
be attributed to reduced availability of the 5-HIAL metabolite rather than to
low levels of
serotonin, as has been previously assumed. The present invention therefore
addresses the
reduced availability of 5-HIAL by administering to the patient a compound
(referred to
from time-to-time as an MAO-A agonist) that increases the catalytic activity
of MAO-A,
thereby increasing metabolism of the serotonin to 5-HIAL. The operative
compound
(MAO-Agonist) is suitably reserpine or a reserpine analogue.
The dose of the reserpine or other operative compound should be sufficient to
metabolize the serotonin to 5-HIAL at a rate that prevents elevated
concentration of non-
metabolized serotonin from developing in the synaptic cleft, as this would
result in too
much serotonin being bound to the transporter, and would in turn result in the
increased
activation of 5-HT1A and therefore decreased release of serotonin and
inhibition of MAO-
A. Yet the dose should not be so high that the synthesis of serotonin is
unable to keep up
with the turnover rate, as this would deplete the stores of serotonin in the
storage vesicles
and result in inadequate release of serotonin into the synaptic clef, which in
turn would
result in inadequate 5-HIAL production and therefore inadequate activation of
the post-
synaptic neuron. Administering too high of dose of the operative compound
consequently
results in an undesirable increase in the symptoms of depression, as has in
fact been
observed, with excessive dosages of reserpine; however, it has been found that
these
symptoms are rapidly resolved upon decreasing the dosage to levels suitable
for the
individual patient.
CA 02591315 2007-06-12
11
b. Comparison with MAO-A Inhibitors and SSRIs
The observed efficacy of the present invention appears to confirm that
inducing an
increase in the metabolism of serotonin to 5-HIAL has a strongly beneficial
effect in
treating mood disorders, and has a profoundly more immediate impact than the
current
antidepressant therapies of MAO inhibitors, tricyclic antidepressants, and
serotonin
reuptake inhibitors. Furthermore, as noted above, intentionally increasing
metabolism of
serotonin runs directly contrary to the conventional belief regarding the
etiology of
depression. Yet, it is incontestable that MAO inhibitors, tricyclic
antidepressants, and
serotonin reuptake inhibitors also produce significant benefits when treating
depression.
This apparent contradiction may be explained as follows, making reference to
FIGS. 3A-
3B and 4A-4B:
Research has shown that MAO inhibitors as well as tricyclic antidepressants
(imipramine, clomipramine, amitriptyline, zimeldine, viloxazine,
nortriptyline,
maprotiline, nomifensine, and doxepine) and some serotonin reuptake inhibitors
(fluoxetine, fluvoxamine, citalopram)) demonstrate inhibitory activity towards
both MAO-
A and MAO-B, but with clearly more potent selectivity for MAO-B. Long-term
administration (four weeks or more) of these antidepressants consequently
results in a
significant increase in the inhibition of MAO-B relative to inhibition of MAO-
A.
Furthermore, these antidepressants are competitive inhibitors of MAO-A but
noncompetitive inhibitors of MAO-B (Egashira et al (1996), Gen. Pharmacology
27(5):773-778; Gnerre et al (2001), J. of Pharm & Pharm. 53(8):1125-1130).
Competitive
inhibitors have a more reversible effect, in that saturating concentrations of
the substrate
(such as increased levels of the substrate serotonin or norepinephrine) can
remove the
inhibition, thus negating the MAO inhibitory effect. Noncompetitive
inhibitors, however,
are irreversible and do not compete with the natural substrate, so that an
increased
concentration of the substrate (i.e., serotonin or norepinephrine) does not
negate the MAO
inhibitory effects.
Consequently, as can be seen in FIG. 3A, MAO-A Inhibitors initially inhibit
both
MAO-A and MAO-B, the inhibition of MAO-A being competitive and that of the MAO-
B
being noncompetitive as described above. Inhibition of the MAO-A inhibits
metabolism
CA 02591315 2007-06-12
12
of serotonin to 5-HIAL, so that continued release of serotonin from the
vesicles of the pre-
synaptic neuron results in an increased concentration of serotonin in the
synaptic cleft. As
can be seen in FIG. 4B, the increased serotonin levels in turn compete with
the MAO-A
Inhibitor, resulting in a negation of the MAO-A inhibition.
Thus, it is believed that the conventional antidepressants noted above have
only a
short-acting MAO-A inhibitory effect, because after a few weeks of treatment
the
concentration of the substrates (serotonin or norepinephrine) increase to the
level capable
of negating the MAO-A inhibitory effect, while the MAO-B inhibitory effect
persists
indefinitely. The ultimate result is an increased ratio of MAO-A:MAO-B
activity, with the
MAO-A being proportionally higher. The increased MAO-A levels, in turn, cause
increased metabolism of the serotonin to the metabolite (5-HIAL) that
activates the
receptors of the post synaptic neurons. This would appear to account for the
antidepressant
effect of conventional treatments, and may also explain why there is a lag of
several weeks
before any benefit is seen when using prior antidepressants.
As is shown in FIGS. 4A-4B, the benefits observed with SSRIs and tricyclic
antidepressants may in turn be due to the effect of reducing inhibition of the
release of
serotonin from the pre-synaptic nerve. Inhibition of serotonergic neurons is
mediated by
5-HT 1 A autoreceptors. Serotonin that is not metabolized in the nerve synapse
binds to the
serotonin transporter, which reuptakes the serotonin from the nerve synapse
and carries it
back into the presynaptic serotonergic neuron. This serotonin that is taken
back up into the
presynaptic neuron activates the 5-HT1A autoreceptors in the presynaptic
neuron, resulting
in a decrease in the release of serotonin into the nerve synapse. The
activation of the 5-
HT1A autoreceptors, by the reuptake of the serotonin, also induces inhibition
of the MAO-
A activity, resulting in a decrease in the synapse metabolism of serotonin to
the active
metabolite 5-HIAL (Larsson et al, 1990).
As shown in FIG. 4B, SSRIs and tricyclic antidepressants block the binding of
the
serotonin to the serotonin transporter, which in turn prevents the activation
of the 5-HT 1 A
autoreceptor. As a result, serotonin continues to be released into the
synaptic cleft, from
the storage vesicles in the pre-synaptic neuron, despite already elevated
levels in the cleft.
Furthermore, the metabolism of serotonin into the active 5-HIAL metabolite is
inhibited by
CA 02591315 2007-06-12
13
the SSRIs by competitive inhibition of MAO-A, similar to the effect of the MAO-
A
inhibitors described above.
The net result is a significant increase in the concentration of serotonin in
the
synaptic cleft. After a period of delay, the elevated serotonin concentrations
induce
additional MAO expression, and furthermore the increased concentration of
serotonin
results in a negation of the MAO-A inhibitory effect of the SSRI. SSRIs (like
the MAO
inhibitors) are also non-competitive inhibitors of MAO-B, so that irreversible
inhibition of
MAO-B also results in an increased ratio of MAO-A:MAO-B activity. These
effects
become more pronounced the longer the therapy is administered, finally
resulting in
increased 5-HIAL levels. This would appear to explain the beneficial effects
of SSRIs, and
why there is again usually a lag of several weeks before such effects are
seen.
5-HT 1 A autoreceptors have been shown to be genetically expressed twofold
higher
in depressed patients and fourfold higher in completed suicide cases (Lemonde
et al
(2003), J. of Neurosci. 23(25):8788-8799). Consistent with the above
explanations, the
known genetic link to expression of the 5-HT 1 A autoreceptors, coupled with
the fact that
high levels of estrogen will inhibit MAO-A activity (Youdim et al (1989),
FASEB Journ.
4(6):1753-1759; Chevillard et al (1981) Brain Res. 222(1):177-181), may
explain the
genetic and gender prevalence of depressive disorders. Research has also shown
that the
ratio of MAO-A:MAO-B activity decreases with age (Fowler et al (1980), J. of
Neur.
Trans. 49(1-2):1-20), which may explain the prevalence of depression in the
elderly.
c. Method of Present Invention
The present invention provides a method for treatment of depression and other
mood disorders, by the application or administration of a compound (which may
be
referred to for purposes hereof as an MAO-A agonist) that increases the
catalytic activity
of MAO-A in metabolizing serotonin to its active metabolite 5-HIAL. Suitable
compounds includes reserpine and reserpine analogues; as used herein, the term
"reserpine
analogue" refers to compounds having a pharmacological effect similar to
reserpine, in
effecting an increase in the catalytic activity of MAO-A. Reserpine in
particular has been
shown to activate MAO-A, as well as to inhibit aldehyde dehydrogenase (Youdim
&
CA 02591315 2007-06-12
14
Sandler (1968) Eur. J. of Pharm. 4:105-108). It is anticipated that other
rauwolfia
alkaloids and their analogues may also be useful.
The treatment composition of the present invention may be administered by any
suitable means, such as orally, or by transdermal application, or injection,
or inhaler, to
give just a few examples. However, administration by transdermal application
is generally
preferred, in that this provides significant advantages in terms of ease of
use and more
consistent dosage levels.
Accordingly, a preferred composition for use in the treatment of the present
invention is formed by the preferred MAO-A agonist reserpine in a transdermal
cream.
When transdermally administered, daily dosage is significantly less than 0.03
mg/day and
preferably within the range of about 0.002-0.02 mg/day, with a range of about
0.006-0.01
mg/day being most preferred. The treatment composition is suitably applied in
a single
daily dose, e.g., 0.0 1 mg of the MAO-A agonist in 0.05 ml of transdermal
cream applied
once every morning. Caffeine may also be included in the composition to
compensate for
the anti-hypertensive effect of the preferred reserpine; the caffeine may
suitably be
included in an amount from about 50-100 mg/dose.
As has been explained above, the present invention differs profoundly from
previous methods used for treatment of depression. Based on the prior theories
and
antidepressant treatments, administration of any agent that would enhance the
metabolism
of serotonin would be strongly contraindicated. Current conventional
antidepressant
medications are aimed at increasing the levels of serotonin: The MAO
inhibitors are aimed
at preventing, rather than increasing, metabolism of serotonin, which the
tricyclic
antidepressants and serotonin reuptake inhibitors are similarly aimed at
maintaining higher
levels of serotonin in the nerve synapses. The use of a MAO-A agonist
therefore runs
directly contrary to the purpose of both types of treatment, and even more so
against the
recent trend toward the use of specific MAO-A inhibitors as a treatment for
depression. In
point of fact, the drug information reference "Facts and Comparisons 2002"
states
expressly that reserpine is contraindicated in mental depression, or where
there is a history
of mental depression, especially with suicidal tendencies.
CA 02591315 2007-06-12
5 d. Examples
The following illustrative examples relate to actual practice of the invention
described above, and its success in alleviating the symptoms of depression and
facilitating
the cessation of substance abuse.
EXAMPLE ONE
A 44-year old, 250-pound male suffering from depression was treated in
accordance with the method of the present invention. The patient reported
suffering from the following persistent symptoms of depression for four years
prior
to treatment.
= Persistent anxious mood
= Feelings of hopelessness, pessimism
= Feelings of guilt, worthlessness
= Loss of interest or pleasure in hobbies and activities that were once
enjoyed
= Decreased energy, fatigue
= Difficulty concentrating, remembering, making decisions
= Insomnia, early-morning awakening, daytime sleeping
= Overeating and weight gain
= Thoughts of death or suicide
= Persistent physical symptoms that do not respond to treatment--
headaches and gastric upset
= Inability to stop drinking until inebriated if offered alcohol
Treatment was in the form of 0.01 mg of reserpine per 0.05 ml of transdermal
cream, applied transdermally once a day in the morning. Within four hours of
the
first application of the treatment, the patient reported a significant
improvement in
his state of mind, and that the negative outlook and emotions identified above
had
resolved. The patient has continued on the treatment, and remains free of all
of the
prior symptoms so long as the consecutive 24-hour dosing regimen is followed.
Moreover, he has ceased overeating and has lost in excess of 20 pounds during
the
treatment. In instances where the patient has forgotten to take the dose for a
day,
symptoms have begun to return within about 32 hours of the last dose
administered
(reserpine has a 33 hour therapeutic half-life in the human body). When the
dose
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was missed for 72 hours, the patient displayed agitation, difficulty
concentrating,
feelings of worthlessness and pessimism; however, within one hour of applying
the
missed dose, the patient was free of all symptoms. The patient has had an
occasional beer or mixed drink while socializing with friends during the
treatment,
but often has not even finished the drink.
EXAMPLE TWO
A 44-year old, 175-pound female suffering from depression was treated in
accordance with the method of the present invention. The patient reported
suffering from the following persistent symptoms of depression for 15 years
prior
to treatment:
= Persistent sad mood with frequent episodes of weeping for no reason
= Feelings of hopelessness and pessimism
= Feelings of helplessness
= Decreased energy, fatigue
= Difficulty concentrating, remembering, making decisions
= Insomnia
= Overeating and weight gain
= Persistent physical symptoms that do not respond to treatment--
headaches, acne, and hair loss.
The treatment consisted of 0.01 mg of reserpine per 0.05 ml of cream, applied
transdermally by rubbing the cream into the skin once a day in the morning.
Within one hour of applying the dose the patient reported increased energy;
she
developed a headache and some nausea that persisted for the first eight hours
after
initiation of the treatment, but then spontaneously resolved. Within 10 hours
of the
first application the patient reported all perceptible symptoms had resolved,
with
the exception that she still had some slight problems with memory. The patient
continued on the treatment for 30 consecutive days with no return of her
symptoms
during that time. The patient averaged weight loss of one to two pounds per
week
during the 30-day course of treatment. The treatment was interrupted for 10
days at
the end of the first 30 consecutive-day treatment; all of the symptoms
returned
during this period of abstinence from the treatment, and the weight loss
halted
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despite no marked change in her diet. The patient then resumed the treatment,
and
within one hour of doing so she reported that her symptoms had again resolved.
She also resumed the 1-2 pound per week weight loss. She lost a total of 15
pounds during the first 50 days, and continues on treatment.
EXAMPLE THREE
A 20-year old, 220-pound male suffering from depression and substance
abuse (marijuana use twice a day, and consumption of alcohol to the point of
inebriation about twice a week) had tried unsuccessfully to stop the substance
abuse several times in the preceding three years. The longest period he was
able to
abstain from smoking marijuana was two weeks, due to "intense cravings". The
patient reported suffering from the following persistent symptoms of
depression for
5 years prior to treatment:
. Persistent sad and "empty" mood
= Feelings of pessimism
= Decreased energy
= Insomnia
= Overeating and weight gain
= Thoughts of death but not suicide
= Persistent physical symptoms that do not respond to treatment--
headaches and stomach cramps
The treatment consisted of 0.01 mg of the reserpine per 0.05 ml of cream,
applied
transdermally by rubbing the cream into the skin once a day in the morning.
Within two hours of applying the first dose all of the pessimism and negative
mood
aspects listed above resolved, and he also reported experiencing no cravings
for
marijuana or alcohol. On the third day of treatment, the patient reported some
feelings of sadness and decreased energy; the dose was then decreased to
0.0075
mg of reserpine, and the symptoms resolved that same day. He has not used any
marijuana during the treatment and he reports having no cravings for the
substance.
He does have an occasional single beer, about twice a month, but he reports no
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desire to drink alcohol. He lost five pounds during the first 60 days and
continues
on the treatment.
EXAMPLE FOUR
A 64-year old female with a family history of depression and a personal
history of major clinical depression, who had been hospitalized in 1975 and
again
in 1990 with major episodes of depression, including extreme suicidal
ideations.
Numerous different medications were tried in an effort to stabilize her
condition,
with only limited success. Since 1990 she had been taking 25 mg to 75 mg of
nortriptyline to manage her depression, and reported having to increase the
dose to
as high as 100 mg during stressful life events. The patient experienced dry
mouth
and constipation as side effects of using nortriptyline. The patient reported
suffering from the following symptoms, despite taking nortriptyline:
= Decreased energy, fatigue
= Early morning awakening
The patient discontinued the use of nortriptyline and the same day started the
treatment of the present invention, using 0.01 mg of the reserpine per 0.05 ml
cream, applied transdermally by rubbing the cream into the skin once a day in
the
morning. Within one hour of applying the first dose the fatigue and loss of
energy
resolved. She reported increased energy throughout the day and she did not
experience tiredness in the evening as per usual on the nortriptyline. Early
in the
treatment she reported that she was going through a very stressful time in her
life,
that in the past would have required her to increase her dose of nortriptyline
as high
as 100 mg in order to cope with the stress, but she has not had to increase
the
dosage when using the treatment of the present invention. After 10 months of
consecutive daily treatment using 0.01 mg of the MAO-A activity stimulator
(reserpine) per 0.05 ml cream applied transdermally, with no return of the
symptoms listed above, the patient experienced some insomnia and fatigue
during a
prolonged, very stressful event (a lawsuit). The patient increased the dose to
0.02
mg of the MAO-A activity stimulator for one week, and insomnia and fatigue
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resolved. After the stressful event was completed, the patient returned to the
0.01
mg dose of the MAO-A activity stimulator, with no return of any symptoms of
depression.
EXAMPLE FIVE
A 24-year old female weighing 180 pounds with a clinical diagnosis of
depression. This patient had been using a serotonin reuptake inhibitor (SSRI)
for
three months with moderate effect in alleviating her symptoms of depression,
with
the exception of labile emotions consisting of transient irritability. The
patient
experienced a 15-pound weight gain while using the serotonin reuptake
inhibitor.
Due to the weight gain, the patient had discontinued the use of the serotonin
reuptake inhibitor for a period of two months prior to starting the treatment
of the
present invention. She reported that during this lapse in treatment all of her
symptoms of depression had returned, which included:
= Insomnia
= Fatigue throughout the day
= Labile emotions including irritability and spontaneous crying
= Feelings of hopelessness and "doom and gloom"
The patient then started the treatment of the present invention, using 0.01 mg
of the
MAO-A activity stimulator (reserpine) per 0.05 ml cream, applied transdermally
by
rubbing the cream into the skin once a day in the morning. The patient
experienced
a headache that did not resolve spontaneously the first day, so the dose was
reduced
to 0.002 mg the second day. The headache resolved immediately with the lower
dose of 0.002 mg and the patient reported alleviation of her symptoms of
feeling
hopelessness and "doom and gloom", but her other symptoms persisted. On the
third day the dose was therefore increased to 0.004 mg of the MAO-A activity
stimulator; in response, she reported improvement in her emotions stating, "I
don't
cry at the drop of a hat". At the 0.004 mg dose (reserpine) level her feeling
of
hopelessness was alleviated, and she was more emotionally stable as well, but
she
still experienced fatigue and insomnia. The does was consequently increased to
0.006 mg per day, at which point all of the patient's symptoms of depression
were
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successfully alleviated. She has been on the treatment for eight consecutive
months, using
0.006 mg per day of the reserpine applied transdermally, with no return of the
symptoms of
depression listed above.
It will be noted that in each of the examples the improvement or resolution of
5 symptoms was essentially immediate, occurring within 1-4 hours of the
first application of the
treatment composition. This stands in dramatic contrast to the delay of 2-3
weeks characteristic
of conventional treatments. Moreover, in all examples, the treatment has
proceeded with no
significant negative side effects; the preferred reserpine (and other
rauwolfia alkaloids) have
known negative side effects at higher dosage rates, however, the dosage rates
used in the
10 method of the present invention are well below those ranges. Moreover,
the preferred MAO-A
activity stimulator - reserpine - is comparatively economical, so that the
invention can be
practiced without prohibitive expense.
The scope of the claims should not be limited by particular embodiments set
forth
herein, but should be construed in a manner consistent with the specification
as a whole.
