Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND COMPOSITIONS FOR TREATING AND
PREVENTING CERTAIN PSYCHIATRIC
AND MEDICAL DISORDERS USIrIG MOCLOHEMIDE
This application incorporates by reference herein
United States application 60/094,985, filed July 31, 1998.
1. FIELD OF THE INVENTION
This invention relates to methods and compositions
for treating or preventing low affect disorders, which are
characterized by malaise and lethargy. Such low affect
disorders may be associated with a general psychological or
medical condition. This invention also relates to treating
partial therapy-refractory depression, partial therapy-
refractory atypical depression, and adolescent depression.
The invention further relates to a method for treating
malaise, lethargy, hypersomnia, weight gain, carbohydrate
craving, obesity, overeating, leaden paralysis, rejection
sensitivity, sexual inhibition, somatoform disorder,
somatised symptoms, learning disability, conduct disorder,
oppositional defiant disorder or conduct disturbance either
individually or in combination, with moclobemide, a
moclobemide metabolite, a moclobemide derivative, or a
moclobemide composition.
2. BACKGROUND OF THE INVENTION
2.1. CHEMISTRY ANL~ PHARMACOKINETICS OF MOCLOHEMIDE
Moclobemide, or p-chloro-N-(2-morpholinoethyl)-
benzamide, which is represented by the formula:
O
CI CI-NH-CH2-CH2-N
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is described in U.S. Patent No. 4,210,754, to Burkard et al.
Moclobemide is a selective and reversible monoamine
oxidase (MAO) subtype A inhibitor. Kettler, R. et al., 1990,
Acta Psychiatr. Scand , Supp. 360(82):101-103. Unlike other
monoamine oxidase inhibitors, which irreversibly and non
selectively bind MAO and can have severe food and drug
interactions that limit their therapeutic utility,
moclobemide is part of a distinct class of selective MAO
inhibitors that inhibit predominantly or selectively either
monoamine oxidase A (MAO-A) or monoamine oxidase B (MAO-B).
Compounds that selectively inhibit MAO-B, and thereby inhibit
the degradation of dopamine, are useful for the treatment of
neurological and neurodegenerative diseases of the
dopaminergic pathway, such as Parkinson's disease.
Livingston, M.G. and Livingston, H.M., 1996, Druq Safety,
14(4):218-227. Compounds that selectively inhibit MAO-A
predominantly affect the degradation of serotonin and
norepinephrine, leading to increased concentrations of these
neurotransmitters in synapses, and are useful for depression.
Livingston and Livingston, 1996.
The in vitro binding of moclobemide to MAO-A is
weak, but more than 167-fold more selective than for the MAO-
B isozyme. The ex vivo binding of moclobemide to MAO-A has
been demonstrated to be reversible, with sufficient
dissociation to result in recovery of enzyme activity within
16 hours. Fulton, B. and Benfield, P., 1996, Druas,
52(3):451. This is in contrast to older, nonselective and
irreversible MAO inhibitors (also referred to herein as
"irreversible MAOIs" or "IMAOIs"), which irreversibly bind to
either or both MAO-A and MAO-B isozymes and exhibit enzyme
inhibition lasting several days. Da Prada, M. et al., 1990.
As the MAO-A inhibition in vivo is relatively short in
duration, it is generally accepted to be reversible. Da
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Prada et al., 1990, Acta Psychiatr Scand , Suppl.
360(82}:103-105. .
The effects of moclobemide on monoamine metabolism
and/or activity of monoaminergic neurons have been indirectly
demonstrated in humans by reductions in plasma levels of the
catecholamine metabolites homovanillic acid, 3,4-
dihydroxyphenylacetic acid, and 3-methoxy-4-
hydroxyphenylglycol and the serotonin (5-hydroxytryptamine)
metabolite 5-hydroxyindoleacetic acid. In vitro, moclobemide
has no appreciable affinity for muscarinic, dopaminergic,
serotonergic, adrenergic, H1-histaminergic, benzodiazepine or
opioid receptors. Da Prada et al., 1981, Excert~t-a Medica,
183-196; Da Prada et al., 1983, Mod. Probl. Pharmacopsych ,
19:231-245; Da Prada et al., 1984, Clin. Neuropharmacol , 7
(Suppl. 1):684-685.
Moclobemide is extensively distributed in the body
and rapidly eliminated from plasma by metabolic conversion in
the liver. After single-dose oral administration,
moclobemide is almost completely absorbed; however,
bioavailability ranges from 44% to 69% because of substantial
first-pass metabolism. Guentert, T.W. et al., 1990, Acta
Psvchiatr. Scand., Suppl. 360(82):91-93. After multiple
administrations, moclobemide displays increased
bioavailability (approx. 85%), possibly due to saturation of
first-pass metabolism. Id. Moclobemide is metabolized to at
least 19 different metabolites, one of which has moderate
MAO-A inhibitory activity. Jauch, R. et al., 1990, Acta
Psvchiatr. Scand., Suppl. 360(82}:87-90. Age and renal
function are reported to have no significant effect on the
pharmacokinetics of moclobemide; however, elimination is
impaired in patients with hepatic dysfunction. Stoeckel et
al., 1990, Acta Psychiatr. Scand , Suppl. 360(82):94-97.
Thus, patients suffering from liver impairment should receive
only 50% of the normal dosage. Id.
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One of the most attractive features of moclobemide
is its impressive safety profile. Because it does not
permanently inhibit the monoamine oxidase enzyme, it has a
relatively brief pharmacological action that contributes to
its clinical safety. Moclobemide's short plasma half life (1
to 2 hours) also contributes to its safety because it
promptly degrades in the tissues thereby preventing local
over-accumulations. Stoeckel et al., 1990. Moclobemide
appears to produce fewer adverse events in normal clinical
use than other reversible MAGI compounds. Priest,. R.G., et
al., 1995, J. Clin. Psychot~harm , 15(4), Suppl. 2: 1S-3S.
The most frequently reported adverse events were psychiatric,
neurologic, and gastrointestinal disorders, with
hepatobiliary events occurring only rarely (Hilton, S. et
al., 1995, J. Clin. Psvchopharmacol , 15(4 Suppl. 2):76S-
83S), and the effects of moclobemide on the sleep of healthy
volunteers appear weak in comparison to other MAO inhibitors.
Blois, R. et al., 1990, Acta Psychiatr Scand , Suppl.
360 (82) :73-75.
Although moclobemide has not been extensively used
in the United States, it has been used in Europe and in other
countries and it is not known to produce any clinically
relevant interactions with commonly prescribed drugs.
Zimmer, R. et al., 1990, Acta Psychiatr. Scand , Suppl.
360(82):84-86. Moreover, moclobemide is far less likely than
traditional MAO inhibitors to induce hypertensive reactions
with the concomitant administration of sympathomimetic drugs,
or consumption of tyramine-rich foods. Hilton, S.E., 1997,
Eur. Arch. Ps chiatrv Clin Neurosci , 247:113-119; Zimmer,
1990, Acta Psvchiatr. Scand , Suppl. 360(82):81-83; Zimmer,
Fischbach et al., 1990, Acta Psvchiatr. Scand , Suppl.
360(82):76-77; Zimmer, Puech et al., 1990, Acta Psychiatr.
Scand., Suppl. 360(82):78-80; Da Prada et al., 1990, Acta
Psvchiatr. Scand , Suppl. 360(82):106-107. A number of
studies also suggest that moclobemide is better tolerated
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than other compounds with anti-depressant activity. Priest,
R.G., et al., 1995. Perhaps most impressively, the fatal
toxicity index of moclobemide approaches zero. Hilton et
al., 1995.
Initially, the recommended doses for moclobemide
therapy (i.e., to treat depression) were approximately 100 mg
to 150 mg three times daily. Guentert, T.W. et al., 1990.
Subsequent experience has suggested that, in view of the
positive dose-response curve found with moclobemide, doses as
high as 600 mg daily are increasingly efficacious and remain
well-tolerated. Fitton, A. et al., 1992, Druas, 43(4):561-
596.
Moclobemide's excellent safety and positive
tolerance profile have made it a popular anti-depressive in
Canada, Europe, Australia, New Zealand, South Africa, and
Latin America. Angst J. et al., 1996, Int. Clin.
Psychopharmacol., 11(Suppl. 3):3-7; Glick, I.D. et al., 1995
Schatzberg, A.F. and Nemeroff, C.B. (Ed.), The American
Psychiatric Press Textbook of Psvchopharmacologv, Washington,
DC, pp. 839-846)). Prescribing medications such as
irreversible MAOI's with potentially harmful or deadly side
effects to treat depression has traditionally caused some
measure of concern among physicians, who worry that depressed
patients may attempt suicide with the very medicines they are
prescribing. Although moclobemide is an MAO inhibitor, as an
anti-depressive, it appears to be less prone to deadly drug
and food interactions and less toxic in overdose. Patients
taking other MAO inhibitors must adhere to restrictive diets
which require the avoidance of, inter alia, red wines, beer,
aged cheese and meats, liver, yeast extracts and fava or
broad beans.
Furthermore, because moclobemide's side-effect
profile is so benign, it enjoys good compliance rates.
Priest, R.G., 1990, Acta Psychiatr. Scand , Suppl.
360(82):39-41. Compliance is an integral component of
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successful treatment because the morbidity and mortality
rates associated with untreated psychiatric illness are high.
If a patient persistently rejects medical treatment for
psychiatric illness because the initial experience in
pharmacological intervention was bad, then the prognosis can
be just as poor as if the patient had not been treated at
all. When used in the treatment of major depression,
moclobemide has proved itself an effective, gentle, patient-
friendly drug.
2.2. THERAPEUTIC EFFICACY OF MOCLOBEMIDE
Moclobemide, sold under the tradename AURORIXTM or
MANERIXT~" (F. Hoffman-La Roche, Basel, Switzerland), has been
shown to be effective in the treatment of various psychiatric
disorders. For example, moclobemide is marketed in Canada,
Europe, Australia, New Zealand, South Africa, and Latin
America as an antidepressive agent, for which it has
demonstrated significant therapeutic effect in certain
patient populations. Angst J. et al., 1996; Glick, I.D. et
al., 1995. A review of the pharmacological properties and
therapeutic use of moclobemide in depressive illness was
published by Fulton and Benfield in Druas, 52(3):450-478,
1996, updating a previous review of Fitton et al., 1992,
Drugs, 43(4):561-596.
The preparation and use of moclobemide as an anti-
depressant is described in United States Patent No. 4,210,754
to Burkard et a1. In the treatment of depression,
moclobemide has been shown to have similar efficacy to
tricyclic antidepressants (TCAs), selective serotonin
reuptake inhibitors (SSRIs), and nonselective, irreversible
MAO inhibitors. Fulton and Benfield, 1996; Fitton et al.,
1992. In particular, moclobemide has been shown to be
effective in treating elderly patients suffering from
depression or age-related dementia. Wesnes, K. et al., 1990,
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Acta Psvchiatr. Scand , Suppl. 360(82):71-72; United States
Patent No. 4,906,626 to Amrein et a1.
Moclobemide has also been reported to be effective
in the management of tobacco addiction (PCT publication WO
95/28934; PCT publication WO 90/04387), attention deficit
disorder (Trott, G.E. et al., 1992, Psychopharmacol , 106
Supp1.:134-136), and anxiety disorders such as social phobia,
obsessive-compulsive disorder and panic (United States Patent
No. 5,371,082 to Versiani et al.; Liebowitz, M.R. et al.,
1990, Acta Psychiatr. Scand , Suppl. 360(82):29-34; Angst,
J. et al., 1996, Int. Clin. Psychot~harm , 11(Suppl. 3):3-7;
Pollack, M.H. and Gould, R.A., 1996, Int. Clin. Psvchopharm ,
11 (Suppl. 3) :71-75) .
The use of irreversible monoamine oxidase
inhibitors (MAOIs) has been limited by the wide range of
MAOI-drug and MAOI-food interactions that are possible,
particularly with sympathomimetic medications or tyramine-
containing foods, resulting in hypertensive reactions.
Despite their clinical benefits, this has led to a reduction
in use of such medications. Even when MAOI efficacy is
documented for a given condition, many practitioners are
reluctant to prescribe drugs from this class because of the
risk of serious adverse reactions. This appears to be so
even when MAOIs are more effective than other available
treatments. Perhaps due to its classification as a monoamine
oxidase inhibitor, moclobemide has not been extensively
studied in the United States. In fact, moclobemide is not
approved by the U.S. Food and Drug Administration. Further,
there remains a great need in the field of psychiatry for
additional therapies to better treat the growing number of
psychiatric and psychological disorders presently described
in the Dia4nostic and Statistical Manual of Mental Disorders,
Ed. 4, (DSM-IV), American Psychiatric Association, 1994,
Washington, DC. There also remains a need in the field of
medicine for additional therapies to treat psychiatric or
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psychological illnesses or manifestations of other medical
illnesses that are not defined by DSM-IV, such as some mood
disturbances, conduct disturbances, etc.
2.3. DEPRESSION
The term "depression" is a clinically discernable
condition generally known in the art as a depressed mood or a
marked loss of interest or pleasure in nearly all activities
lasting for a period of time (i.e., weeks, months, or years).
Depression (also known as "major depression") is defined in
l0 DSM-IV as five or more symptoms present over at least a two
week period, wherein at least one of the symptoms must be
depressed mood or loss of interest or pleasure and the other
symptoms are selected from the group consisting of: (1)
depressed mood most of the day, nearly every day; (2)
markedly diminished interest or pleasure in all, or almost
all, actvities most of the day, nearly everyday; (3)
significant weight loss when not dieting or weight gain or
decrease or increase in appetite nearly every day; (4)
insomnia or hypersomnia nearly every day; (5) psychomotor
agitation or retardation nearly every day; (6) fatigue or
loss of energy nearly every day; (7) feelings of
worthlessness or excessive or inappropriate guilt nearly
every day; (8) diminished ability to think or concentrate or
indecisiveness nearly every day; and (9) recurrent thoughts
of death, recurrent suicidal ideation without a specific
plan, or a suicide attempt or a specific plan for committing
suicide.
A condition that presents similar symptoms but
arises from, for example, a general medical condition or a
direct physiological effect of taking a substance should not
necessarily be considered depression. In DSM-IV, for
example, a Mood Disorder Due to a General Medical Condition
is a diagnosis made based on history, laboratory findings, or
physical examination, wherein the mood disturbance is judged
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to be a direct physiological consequence of a specific
general medical condition (e. g., multiple sclerosis, stroke,
hyperthyroidism) (pp. 325, and 366-367 of DSM-IV).
Similarly, a Substance-Induced Mood Disorder is
distinguishable from depression by the fact that a substance
(i.e., a drug of abuse, a medication, or a toxin) is judged
to be etiologically related to the mood disturbance (pp. 325-
326, and 370-371 of DSM-IV). DSM-IV also distinguishes an
Adjustment Disorder With Depressed Mood due to, for example,
Bereavement, or periods of sadness from depression.
The criteria for diagnosing depression does not
include the appearance of the symptoms: malaise or lethargy.
There is a need for methods and compositions for treating
illnesses, characterized by the symptoms malaise and
lethargy, especially in patients who are not clinically
depressed or are subclinically depressed. Applicants have
solved this problem by providing methods and compositions for
treating and preventing illnesses characterized by malaise
and lethargy. Illnesses characterized by malaise and
lethargy are described herein as low affect disorders or LAD,
described in more detail below.
2.4. ATYPICAL DEPRESSION
The diagnosis term referred to as "atypical
depression" (AD) has undergone dramatic changes since its
initial exposition. As initially applied to depression,
atypical was synonymous with nonmelancholic, i.e., absent the
usual features of depression such as weight loss and
insomnia, and displaying other symptoms normally absent in
depression, such as anxiety. Lam, R.W, and Stewart, J.N.,
1996, Comprehensive Psychiatry, 37(6):375-383.
Accordingly, the term "atypical depression" (AD)
was originally used to describe depressed patients who were
agitated, psychotic, and responsive to electroconvulsive
therapy. Huston, P.E., and Locker, L.M., 1948, Arch. Neurol.
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Psvchiatry, 60:37-48. West and Dally later applied the term
to a different subset of depressed patients with prominent
phobic anxiety and lack of melancholic vegetative symptoms
such as insomnia and weight loss. West, E.D. and Dally,
P.J., 1959, Br. J. Med., 1:1491-94. They found that such
patients were responsive to the MAOI iproniazid. Id. A
similar patient group was described by Klein, in Liebowitz,
M.R. and Klein, D.F., 1979, Psvchiatr. Clin. North Am ,
2:555-575, as suffering from "hysteroid dysphoria," a
l0 syndrome characterized by marked dysphoric responses to
interpersonal rejection. Along with dysphoria, these
patients also experienced hypersomnia, hyperphagia, and/or
leaden paralysis.
Despite a developing clinical interest in AD, and
advances in defining criteria of inclusion, DSM-III did not
include any specific concept of AD. American Psychiatric
Association, Diagnostic and Statistical Manual of Mental
Disorders, Ed. 3, Washington, D.C., American Psychiatric
Association, 1980. Rather, the modifier "atypical" was used
to denote depression that did not meet the formal criteria
for any depressive diagnostic category. The revised edition,
DSM-III-R, eliminated all reference to atypical depression.
American Psychiatric Association, Diagnostic and Statistical
Manual of Mental Disorders, Ed. 3 Rev., Washington, D.C.,
American Psychiatric Association, 1987.
Even though AD has been recognized as a distinct,
clinically-identifiable syndrome, conflicting definitions
continue to be used in the literature. Some groups use the
term AD to describe depression with phobic anxiety, while
others use AD to describe depression with reverse vegetative
features. Davidson et a1. formalized these two definitions
into A-type and V-type AD, respectively. Davidson, et al.,
1982, Arch. Gen. Psychiatry, 39:527-534. A-type atypical
depressives were described as anxious phobic, tense, and more
prone to atypical pain, whereas V-type depressives had
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increased appetite and weight, increased libido, increased
sleep, mood lability, and irritability. Id.
Research interest in defining AD subsequently
shifted away from a concept primarily involving a lack of
features normally associated with depression, and towards one
defined by the presence of so-called "reverse" vegetative
symptoms, such as weight gain and hyposomnia. Lam and
Stewart, 1996. Accordingly, more recent work on AD has
identified the following clinical criteria: (1) Research
Diagnostic Criteria (RDC) for major, minor, or intermittent
depression, (2) mood reactivity, and (3) two or more of
hypersomnia, weight gain, leaden paralysis, and rejection
sensitivity (hereinafter referred to as the "Columbia
criteria AD"). Stewart, J.W. et al., 1989, Arch. Gen.
Psychiatry, 46:1080-1087; Quitkin, F.M. et al., 1984, J.
Clin. Psychiatry, 45:19-21; Quitkin, F.M. et al., 1993, Br.
J. Psychiatry, 163(Suppl):30-34; Stewart, J.W. et al., 1993,
Psvchiatr. Clin. North Am , 16:479-495.
With two revisions, these criteria have been
incorporated into the DSM-IV; increased appetite is included
alongside weight gain as an alternative symptom within the
third class of symptoms, and a long-standing pattern of
interpersonal rejection sensitivity replaces acute
hypersensitivity during episodes of mood disturbance ("DSM-IV
AD"). Thus, DSM-IV defines AD as a mood reactive depression
with associated reverse vegetative symptoms or marked
interpersonal rejection sensitivity. DSM-IV includes AD as
an episode specifies for major depressive episodes or
dysthymia. The AD mood specifies can be used for depressive
episodes occurring either in unipolar and bipolar mood
disorders. As referred to herein, "DSM-IV AD" is used
interchangeably with "Columbia Criteria AD" to refer to AD
meeting the criteria identified in either or both of the
foregoing paradigms.
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Some studies have found earlier onset of
illness in DSM-IV AD as compared to patients viith typical
depression (Stewart et al., 1993; Davidson, J. et al., 1989,
Comer. Psychiatry, 30:357-368; Thase, M.E. et al., 1991,
Psvchopharmacol. Bull , 27:17-22), but others have found no
difference (Asnis, G.M, et al., 1995, Am. J. Ps~rchiatry,
152:31-36). Similarly, index episode duration has been
reported as longer and more chronic in some studies (Stewart
et al., 1993; Davidson et al., 1989), but not in others
(Asnis et al., 1995). In part, these conflicting and
inconsistent results may be due to the use of different
criteria of inclusion for AD. A longitudinal study of 29
inpatients with AD defined by Columbia criteria found that
only 59% continued to meet these criteria after a 1- to 2-
year follow-up. Ebert, D. and Barocka, A., 1991, Eur. Arch.
Psychiatry Clin. Neurosci , 241:131-132.
The criteria for diagnosing atypical depression,
like those for major depression, does not include the
appearance of the symptoms of malaise and lethargy.
2.4.1. PHARMACOLOGICAL TREATMENT OF ATYPICAL DEPRESSION
Early antidepressant studies suggested that
atypical depressives who met the DSM-IV criteria were
unlikely to respond to tricyclic antidepressants (Bieleski,
R.J. and Friedel, R.O., 1976, Arch. Gen. Psychiatry, 33:1479-
1489; Joyce, P.R. and Paykel, E.S., 1989, Arch. Gen.
Psychiatry, 46:89-99), but showed a good response to MAOI's
(Quitkin, F. et al., 1979, Arch. Gen. Psychiatry, 36:749-
760). However, some studies have not shown differential
responses between MAOI's and tricyclic antidepressants.
Paykel, E.S. et al., 1982, Arch. Gen. Psychiatry, 39:1041-49.
Again, it appears that conflicting criteria may be
responsible for the disparate results. Lam and Stewart,
1996.
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There are few studies on the efficacy of newer
antidepressant medications in treating DSM-IV AD.
Moclobemide has been shown to be effective in treating
Columbia criteria AD or DSM-IV AD in studies comparing it to
other antidepressants, e.g., isocarboxazide and clomipramine
(Larsen, J.K. et al., 1991, Acta Psvchiatr. Scand , 84:564-
570), diazepam (Tiller, J. et al., 1989, J. Affective
Disord., 16:181-187; Schweitzer, I. et al., 1989, Int. J.
Clin. Pharm. Res., IX(2):111-117), and fluoxetine and
imipramine (Stratta, P. et al., 1991, Int. Clin.
Psvchopharmacol., 16:193-196; Lonnqvist, J. et al., 1994, J.
Affective Disord., 32:169-177).
There is a need for methods and compositions for
treating illnesses characterized by malaise and lethargy,
especially in patients who are not clinically atypical
depressive.
2.5 REFRACTORY DEPRESSION AND ATYPICAL DEPRESSION
Resistance to antidepressants is an important
problem in treating depressive disorders, involving up to 20~
of patients. Konig and Wolfersdorf, 1997, Pharmacopsvchiat.,
30:93-96. Although the term "therapy resistance" is defined
differently in various studies, it generally describes
patients who show little to no attenuation of symptoms, or
remission, despite treatment with medication at a therapeutic
dosage and duration, and is used accordingly herein. Zajecka
J.M., Annual Meeting of American Psychiatric Association, May
21, 1995, Miami, Florida.
MAOI's have traditionally presented a significant
risk of negative drug interactions with common
antidepressants. Thus, they are generally considered to have
limited utility for the treatment of antidepressant therapy
resistant patients. As discussed above, MAOI's are prone to
negative interactions with sympathomimetic medications,
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resulting in hypertensive shock. The most serious of such
interactions may be fatal. Livingston and Liv~ingston, 1996.
In addition to the threat of hypertensive shock,
MAOI's tend to interact negatively with drugs that enhance
serotonin production or release, such as TCA's. Although the
exact mechanism of interaction is unknown, the co-
administration of the two serotonergic compounds is thought
to cause serotonin syndrome. Sternbach, H., 1991, Am. J.
Psychiatry, 148:705-13. This syndrome is characterized by
restlessness, shivering, diaphoresis, tremor, hyperreflexia
and myoclonus. Drugs that are likely to cause this syndrome
with co-administered conventional MAOIs, in addition to the
TCAs (especially the more serotonin-specific clomipramine),
are the selective serotonin reuptake inhibitors (SSRI),
citalopram, fluoxetine, fluvoxamine, paroxetine, and
sertraline. Some opioids, such as pethidine (meperidine),
may also cause symptoms of the serotonin syndrome when co-
administered with conventional MAOIs, and, sometimes such
combinations cause a central depression syndrome that
involves excessive sedation and ultimately coma and death.
Livingston and Livingston, 1996.
Unlike many MAOI's, moclobemide can be safely and
effectively used in alone or in combination with tricyclic
and tetracyclic antidepressants to treat therapy-resistant or
refractory depression (RD). Stabl, M. et al., 1995; Konig
and Wolfersdorf, 1997. Initial results involving the
coadministration of moclobemide and SSRIs have been varied.
One pilot study described the effective coadminstration of
moclobemide and fluvoxamine (SSRI) to therapy-resistant
patients. [Ebert et al. (1995)] On the other hand, five
cases of fatal intoxications from "serotonin syndrome" after
coadministration of moclobemide and an SSRI have been
reported. [Neuvonen et al., (1993)]
In addition to refractory depression, therapy-
resistant atypical depression or refractory atypical
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depression (RAD) also presents a significant pharmacological
challenge due to the dangerous potential for adverse drug
interactions as described above (e.g., with SSRI's and
TCA's). A patient with RD or RAD can not readily be switched
from the drug to which he has failed to respond or to another
antidepressant. Rather, switching between antidepressants
typically entails a "wash-out period" of several weeks, due
to the relatively long half-lives of many common
antidepressants, to ensure elimination of the prior drug from
the patient's system. Throughout this delay, the therapy-
resistant patient remains untreated, potentially leading to
increased severity of depression and serious psychological
and physiological complications.
Further, there is a need for methods for treating
depressive and atypical depressive patients who partially
respond to antidepressive treatment (hereinafter "partial RD"
or "partial RAD" patients, or PRD or PRAD patients,
respectively), i.e., patients who after antidepressive
therapy experienced a decrease or elimination of some but not
all of their depressive or atypical depressive symptoms such
that they cannot be described as depressive or atypically
depressive under the criteria in DSM-IV. Such PRD or PRAD
patients include those patients who: (1) experience transient
complete recovery from depression or atypical depression; (2)
subsequently develop depression or atypical depression that
is only partially responsive to treatment after 6 months or
who develop one or more of the symptoms of depression or
atypical depression; and (3) cannot be described as
depressive or atypically depressive under the criteria in
DSM-IV. To the best of applicant's knowledge, the efficacy
of moclobemide alone or in combination with other
antidepressants such as TCAs, tetracyclic antidepressants or
SSRIs in treating PRD or PRAD patients has not yet been
demonstrated.
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2.6 ADOLESCENT DEPRESSION
The DSM-IV recognizes that adolescents are
susceptible to certain distinct disorders, such as adolescent
antisocial behavior (DSM-IV, p. 684), attention
deficit/hyperactivity disorder (pp. 78-85), adolescent-onset
type Conduct Disorder (pp. 85-91), and Oppositional Defiant
Disorder (pp. 91-94).
However, "adolescent depression" is a not well-
characterized disorder that afflicts adolescents and includes
specialized symptoms of mood reactivity, social anxiety, and
mood-associated rejection sensitivity or hypersensitivity to
interpersonal rejection. Thus, depressive episodes in
adolescents typically differ in character from those
experienced by adult depressives (DSM-IV, pp. 320-327).
It should be appreciated that, to some extent, the
above-identified symptoms of adolescent depression are
characteristic of adolescence itself, and, in most cases, are
not of an intensity or duration warranting pharmaceutical
intervention. However, in identifying a new syndrome marked
by the above-identified characteristics, it is contemplated
by applicant that adolescents who suffer the above symptoms
to a degree that interferes with their social, psychological,
and interpersonal functioning may be treated without the need
to "wait and see" whether a clinically identifiable diagnosis
develops.
Thus, despite the knowledge about adult depression
and treatments for depression known in the art, there exists
a need for better and alternative methods for treating
adolescent depression, which is different from adult
depression and from known adolescent syndromes described
above. To the best of applicants' knowledge, the use of
moclobemide to treat or prevent depression in adolescents and
especially treat symptoms which may develop into adolescent
depression if left untreated has never been reported.
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2.7 SEXUAh INHIBITION
The human sexual response can generally be divided
into three phases: libido, excitement, and orgasm. It has
been shown that certain antidepressants can have deleterious
effects on any of these three phases. Problems with
excitement may include impotence, painful erection,
spontaneous erection, penile or clitoral priapism, and
difficulty with vaginal lubrication. Problems with orgasm
encompasses delayed orgasm, painful orgasm, anorgasmia,
spontaneous ejaculation, retrograde ejaculation, and
anhedonic ejaculation (ejaculation without orgasm).
[Margolese, H.C. and P. Assalian, J.Sex Marital Ther 22:209-
217 (1996)].
Moclobemide given to healthy volunteers has been
reported to have no effect on sexual desire and function over
placebo. [Kennedy, S.H., et al., Euro. Neuronsychopharmcol
6:17?-181 (1996)]. Other antipressants are known to induce
sexual dysfunction in patients with depression. In one
study, depressive patients treated with fluoxetine
experienced diminished libido, orgasm and/or erection which
was alleviated after fluoxetine treatment ended and
moclobemide treatment began. [Ramasubbu, R., 1999]. In
another case, a patient treated with moclobemide directly
followed by doxepin (an antidepressant) experienced
overreactivity to sexual stimulation 5-7 days after starting
moclobemide treatment and up to 6 days following the
cessation of moclobemide treatment. [H. Lauerma, Int. Clin.
Psvchopharmacol 10:123-124 (1995)]. In yet another case, a
major depressive patient was reported to experience sexual
hyperarousal after treatment with moclobemide. [Philipp, M.
et al., Int. Clin. Psvchospharmacol 7:149-53 (1993)].
Thus, although moclobemide has been suggested to be
involved in the sexual hyperarousal of some patients with
major depression, to the best of applicant's knowledge, the
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use of moclobemide to treat sexual inhibition in patients who
are subclinically depressed or who are not clinically
depressed has never been reported.
3. SUNlHiARY OF THE INVENTION
The present invention relates to the use of
moclobemide, a metabolite of moclobemide, or a derivative of
moclobemide for treating or preventing certain psychiatric
and medical disorders. Moclobemide, or moclobemide
metabolite, or moclobemide derivative according to this
invention may be in the form of a pharmaceutically acceptable
salt, hydrate, or solvate. Hereinafter, the term
"moclobemide, moclobemide metabolite or moclobemide
derivative," includes moclobemide, a metabolite of
moclobemide, or a derivative of moclobemide; or a prodrug of
moclobemide, a metabolite of moclobemide, or a derivative of
moclobemide; or pharmaceutically acceptable salt, hydrate,
solvate of moclobemide, a metabolite of moclobemide, a
derivative of moclobemide; or prodrug thereof. The present
invention also encompasses the use of a composition in the
methods of this invention, wherein the composition comprises
moclobemide, a metabolite of moclobemide, or a derivative of
moclobemide together with a pharmaceutically acceptable
carrier. Moclobemide metabolites according to this invention
are those with MAO-A inhibitor activity, such as moclobemide-
N-oxide.
The invention encompasses the use of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition in treating or preventing certain
disorders associated with low affect as defined herein.
Thus, one embodiment of the present invention relates to the
treatment of low affect disorders by administration of a
therapeutically effective amount of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
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moclobemide composition. Another embodiment of the present
invention is the treatment of disorders associated with LAD,
by administration of a therapeutically effective amount of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition.
The invention also encompasses the use of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to treat or prevent
adolescent depression.
The invention also encompasses the use of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to treat the symptoms
of malaise and lethargy.
The invention also encompasses the use of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition in treating PRD or
PRAD by administration to a patient exhibiting, at a sub-
syndromal level, symptoms commonly associated with the
development of depression or atypical depression, either
alone or in conjunction with psychotherapy. Thus, the
present invention also encompasses methods for treating PRD
or PRAD in a human by administering a therapeutically
effective amount of moclobemide, a moclobemide metabolite, a
moclobemide derivative or a moclobemide composition to said
human.
The invention also encompasses the use of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to treat individual
symptoms commonly associated with atypical depression, such
as hypersomnia, weight gain, leaden paralysis, and rejection
sensitivity, in patients who are not clinically depressed or
who are subclinically depressed. Accordingly, one embodiment
of the present invention is a method for treating a human
with hypersomnia, weight gain, leaden paralysis, and/or
rejection sensitivity by administering a therapeutically
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effective amount of moclobemide, a moclobemide~ metabolite, a
moclobemide derivative or a moclobemide composition, to said
human.
The invention relates to the use of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition to treat a LAD patient, suffering
from sexual inhibition, somatization, somatoform disorder,
carbohydrate cravings, obesity or overeating, who is not
clinically depressed or who is subclinically depressed.
Another object of this invention is to provide a
method for treating or preventing an illness selected from
the group consisting of a learning disability, conduct
disorder, oppositional defiant disorder, or a conduct
disturbance, in a human who is in need of treatment for said
illness and who does not suffer from attention deficit
hyperactivity disorder, comprising the step of administering
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition thereof.
The present invention further encompasses the use
of moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to treat patients who
are immunocompromised or immunosupressed, as a result of, for
example, viral infection including HIV, cancer, medication,
or post-operative trauma. Accordingly, one embodiment of the
present invention is a method for treating LAD in an
immunocompromised or immunosupressed patient by administering
a therapeutically effective amount of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition to said human.
The use of other moclobemide derivatives is also
encompassed by the present invention. In particular, the use
of p-iodo-N-(2-morpholinoethyl)-benzamide, p-fluoro-N-(2-
morpholinoethyl)-benzamide, p-bromo-N-(2-morpholinoethyl)-
benzamide, and p-chloro-N-(2-morpholinoethyl)-benzamide-N~-
oxide is contemplated. Each of these compounds, and salts
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thereof, is structurally similar to moclobemide and can be
used with the present methods, although moclobemide is
preferred.
According to this invention, moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition may be administered before, along
with, or after other psychoactive compounds, particularly
those with antidepressant activity. Accordingly, the present
invention encompasses the use of moclobemide, a moclobemide
metabolite, a moclobemide derivative or a moclobemide
composition to treat or prevent LAD, adolescent depression,
or the above-identified individual symptoms commonly
associated with AD, in conjunction with other known
antidepressants, such as tricyclic antidepressants,
serotonin-reuptake inhibitors, atypical antidepressants and
other monoamine oxidase inhibitors. Such known
antidepressant compounds include, without limitation,
tricyclic antidepressants such as amitriptyline,
clomipramine, doxepin, imipramine, (+)-trimipramine,
amoxapine, desipramine, maprotiline, nortriptyline, and
protryptiline; serotonin-reuptake inhibitors such as (~)-
fluoxetine, (+)-fluoxetine, fluvoxamine, paroxetine,
sertraline, and (~)-venlafaxine or an active optical isomer
thereof; atypical antidepressants such as bupropion,
nefazodone, and trazodone; and other monoamine oxidase
inhibitors, such as phenelzine, tranylcypromine, and (-)-
selgiline, either singly or in combination. In particular,
the present invention encompasses the use of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition in conjunction with other known
antidepressants without the resulting negative drug
interactions commonly associated with MAOI~s.
The present invention further encompasses the use
of moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition in conjunction with
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traditional psychotherapy to treat or prevent LAD, adolescent
depression, PRD or PRAD in a human by administering
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to said human,
before, during, or after psychotherapeutic intervention.
The invention provides for methods for using
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition either alone or in
conjunction with psychotherapy, antidepressants, or
additional psychoactive medication such as lithium, in all
potential human patient populations, including men, women,
children and the elderly.
In one embodiment, the humans to be treated do not
have depression, atypical depression and/or attention deficit
hyperactivity disorder. One preferred class of patients to
be treated with moclobemide, a moclobemide metabolite, a
moclobemide derivative or a moclobemide composition thereof
is immunocompromised or immunosupressed patients.
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4. DEFINITIONS
As used herein, the terms "malaise"and "lethargy"
are as known in the art. For example, malaise can be
characterized by a feeling of discomfort, and lethargy can be
characterized as drowsiness.
As used herein, the term "affect" is defined as
emotional feeling, tone, or mood, including its external
manifestations.
As used herein, the term "low affect" is defined as
emotional tone tending towards sadness, lethargy, malaise,
melancholy, dejection, listlessness, or withdrawal in the
absence of external stimuli, such as reactive depression that
is inappropriate or is abnormally protracted or prolonged
(e.g., wherein the initial cause of the depression is
bereavement) commonly associated with such emotions.
As used herein, the term "low affect disorder"
(LAD) is an affliction with the hallmark characteristics of
malaise and lethargy. LAD is distinguished from depression,
as defined in DSM-IV, by the presence of these characteristic
symptoms, which do not appear in the DSM-IV definition of
"depression". LAD may be present in conjunction with a
general medical or psychological condition, or may be
independent of any additional symptoms. For example, LAD may
be accompanied by symptoms meeting the criteria for RD or
RAD.
As used herein, the terms "not clinically
depressed" or "subclinical depression" refers to a condition
which does not meet the criteria of major depression or
atypical depression according to DSM-IV. The term
"subclinical depression" additionally refers to a condition
as readily known in the art and can be characterized by low
affect .
As used herein, the term "refractory depression" or
"RD" is defined as a syndrome that (1) meets the RDC for
major, minor, or intermittent depression and (2) is resistant
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to treatment with SSRI's, TCA's, or other standard
antidepressant medications after a period of 6~months.
As used herein, the concept of AD has been further
refined to describe a subset of patients nonresponsive to
treatment for AD, as defined by the Columbia criteria or the
DSM-IV criteria. As used herein, "ref ractory AD" or "RAD"
is defined as a syndrome that: (1) meets the Research
Diagnostic Criteria (RDC} for major, minor, or intermittent
depression, (2) includes mood reactivity, (3) includes two
or more of hypersomnia, weight gain, increased appetite,
leaden paralysis, acute, mood-associated rejection
sensitivity,.or a long-standing pattern of hypersensitivity
to interpersonal rejection, and (4) is resistant to treatment
with selective serotonin reuptake inhibitors (SSRI's),
tricyclic antidepressants (TCA's), or other standard
antidepressant medications after a period of 6 months. For
example, a patient with RAD, as defined herein, may be
depressed, display mood reactivity, have an increased
appetite and hypersomnia, and be SSRI-refractory or
nonresponsive after 6 months of treatment with at least one
SSRI, either alone or in combination with other
pharmacological or psychotherapeutic interventions.
As used herein, the term partial RD (or PRD) refers
to a patient who after antidepressive therapy experience
decrease or elimination of some but not all of his/her
depressive symptoms such that he/she cannot be described as
depressive under the criteria of DSM-IV. Such PRD patients
include those patients who: (1) experience transient complete
recovery from depression; (2) subsequently develop depression
that is only partially responsive to treatment after 6 months
or who develop one or more of the symptoms of depression; and
(3) cannot be described as depressive under the criteria in
DSM-IV.
As used herein, the term partial RAD (or PRAD)
refers to a patient who after antidepressive therapy
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experience decrease or elimination of some but- not all of
his/her atypical depressive symptoms such that he/she cannot
be described as atypically depressive under the criteria of
DSM-IV. Such PRAD patients include those patients who: (1)
experience transient complete recovery from atypical
depression; (2) subsequently develop atypical depression that
is only partially responsive to treatment after 6 months or
who develop one or more of the symptoms of atypical
depression; and (3) cannot be described as atypically
ZO depressive under the criteria in DSM-IV.
As used herein, the term "adolescent depression"
describes a novel subset of depressed individuals with unique
manifestations of depression thought to be related to the
complicated social, psychological, and biochemical
environment of adolescence. Thus, adolescent depression is
defined as a syndrome that (1) begins between the ages of 9
and 19, and that includes (2) mood reactivity, (3) social
anxiety, and (4) mood-associated rejection sensitivity or
hypersensitivity to interpersonal rejection. Adolescent
depression according to this invention is distinct from known
adolescent syndromes as descrbed in DSM-IV.
As used herein, the term "sexual inhibition"
describes an inhibition of or deficiency in a sexual
response, i.e., libido, excitement, or orgasm. Sexual
inhibition as used herein does not include inhibition of or
deficiency in a sexual response directly caused by a physical
defect which makes a sexual response physically impossible.
As used herein, the term "somatoform disorder" is
used to describe a group of disorders having clinically
significant physical symptoms that suggest a general medical
condition and are not fully explained by a general medical
condition, by the effects of a substance, or by another metal
disorder (i.e., results in medical treatment or causes
significant impairment in functioning), as defined in DSM-IV
(supra) .
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As used herein, the term "somatization" is used to
describe an unconscious process in a patient not afflicted
with a "somatoform disorder" as defined in DSM-IV, whereby
psychological distress or anxiety is expressed as a physical
symptom (hereinafter "somatised symptom"). The term
"somatised symptom" according to this invention refers to any
symptom resulting from somatization or a somatoform disorder
which is a physical expression of psychological distress or
anxiety. For example, a somatised symptom can be a lack of
energy or the presence of fatigue, muscular aches and pains
or a symptom that occurs in a somatoform disorder such as
nausea, impaired coordination/balance, paralysis, blindness,
deafness, seizures, dissociative symptoms, loss of
consciousness and pain during sexual intercourse,
menstruation or urination.
The term "carbohydrate craving" according to this
invention refers to a clinically significant tendancy to
frequently crave carbohydrate-containing foods (particularly,
carbohydrate-rich containing snack foods such as potato
chips, pastries, cookies), which is well known in the art
(e. g., Wurtman, R.J. et al., Obes. Res. Suppl 4:477S-480S
(1995). Patients suffering from this tendancy do not
necessarily suffer from obesity.
The term "conduct disorder" according to this
invention refers to a repetitive and persistent pattern of
behavior in which the basic rights of others or major age-
appropriate societal norms or rules are violated, as defined
in DSM-IV (supra). As used herein, a patient experiencing a
conduct disorder does not have Attention-
Deficit/Hyperactivity Disorder as defined in DSM-IV.
The term "oppositional defiant disorder" according
to this invention refers to a recurrent pattern of
negativistic, defiant, disobedient, and hostile behavior
toward authority figures that persists for at least six
months, as defined in DSM-IV. As used herein, a patient
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experiencing an oppositional defiant disorder does not have
Attention-Deficit/Hyperactivity Disorder as defined in DSM-
IV.
The term "conduct disturbance" according to this
invention refers to a clinically significant behavior in
patient which~is repetitive and persistent, in which the
basic rights of others or major age-appropriate societal
norms or rules are violated, wherein said patient's behavior
does not meet the criteria of a conduct disorder or
oppositional defiant disorder as defined in DSM-IV. As used
herein, a patient experiencing a conduct disturbance does not
have Attention-Deficit/Hyperactivity Disorder as defined in
DSM-IV. The term "conduct disturbance" according to this
invention refers to a clinically significant behavior in a
patient experiencing conduct disorder, oppositional defiant
disorder or conduct disturbance, which is repetitive and
persistent and violates the basic rights of others or major
age-appropriate societal norms or rules. Said conduct
disturbances according to this invention include aggressive
conduct; causes or threatens physical harm to humans or
animals; non-agressive conduct that causes property loss or
damage; deceitfulness or theft; serious violations of rules;
and negativistic, defiant, disobedient, and hostile behavior
toward authority figures. In one embodiment, said human
having a conduct disturbance or a conduct disorder or
oppositional defiant disorder, does not have Attention-
Deficit/Hyperactivity Disorder.
The term "learning disability" is as known in the
art. In one embodiment, a human with a learning disability
according to this invention does not suffer from attention
deficit hyperactivity disorder.
5. DETAILED DESCRIPTION OF THE INVENTION
"Low Affect Disorder" (LAD) is a heretofore
uncharacterized affliction with the hallmark characteristics
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of malaise and lethargy. LAD is distinguished from
depression, as defined in DSM-IV, by the presence of these
characteristic symptoms, which do not appear in the DSM-IV
definition of "depression". In a one embodiment, the LAD
patient being treated in the methods of this invention is not
clinically depressed or is subclinically depressed.
In identifying a new, clinically significant
constellation of symptoms under the diagnosis LAD, it is
hoped that patients with this distinct group of symptoms may
be treated promptly and effectively, without the need to
"wait and see" if another, clinically significant syndrome
develops. Thus, the main advantage of treating LAD is the
avoidance of resultant psychological syndromes such as
depression, of which LAD may be a precursor syndrome.
It should be appreciated that a diagnosis of LAD
can include patients who suffer from these symptoms as part
of clinically defined syndromes such as depression or
atypical depression. Thus, LAD, as used herein, is meant to
encompass patients with malaise and lethargy who are
suffering from a concomitant medical condition, such as an
autoimmune disorder in which "malaise" is a diagnostic
feature, e.g., systemic lupus. Accordingly, it should be
understood that LAD patients may also suffer from concomitant
psychiatric problems. However, it should also be noted that
LAD is not the same disorder as "depression" known in the art
or defined in DSM-IV. To the best of applicant's knowledge,
the use of moclobemide to treat LAD has never been reported.
The invention encompasses the use of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition to treat the symptoms of malaise and
lethargy. In one preferred embodiment, the patient suffering
from malaise and lethargy is not clinically depressed or is
subclinically depressed.
The present invention also provides a method of
treating LAD in a human, which comprises administering to
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said human suffering from LAD a therapeutically effective
amount of moclobemide, a moclobemide metabolite, a
moclobemide derivative or a moclobemide composition.
The present invention encompasses a method of
treating PRAD or PRD in a human, which comprises
administering to said human suffering from PRAD or RAD,
respectively, a therapeutically effective amount of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition either alone or in
conjunction with psychotherapy or additional psychoactive
medication, in a manner designed to minimize or eliminate any
symptoms associated with depression or atypical depression,
respectively, of a subsyndromal intensity. In one preferred
embodiment, the PRD or PRAD patient is administered a
therapeutically affective amount of moclobemide, a
moclobemide metabolite, a moclobemide derivative or a
moclobemide composition with another therapeutic agent such
as a TCA, a SSRI, a antipsychotic drug.
The present invention encompasses a method of
treating adolescent depression in a human, which comprises
administering to said human suffering from adolescent
depression a therapeutically effective amount of moclobemide,
a moclobemide metabolite, a moclobemide derivative or a
moclobemide composition.
The present invention also encompasses the use of
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to treat individual
symptoms commonly associated with atypical depression, such
as hypersomnia, weight gain, leaden paralysis, and rejection
sensitivity, in patients who are not clinically depressed or
who are subclinically depressed.
As used herein, the concept of AD has been further
refined to describe a subset of AD patients, those with
refractory AD ("RAD"), who are nonresponsive to conventional
treatment with well-known antidepressants, such as SSRI's,
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TCA's or other known antidepressants. Thus, a~patient with
RAD, as defined herein, would continue to meet the DSM-IV or
Columbia criteria for AD after 6 months of treatment with at
least one antidepressant.
The invention provides a method for using
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to a patient, who is
not clinically depressed or who is subclinically depressed,
and who is suffering from~sexual inhibition, somatization,
somatoform disorder, carbohydrate cravings, obesity or
overeating. The invention also provides a method for
treating a somatised symptom comprising the step of
administering moclobemide, a moclobemide metabolite, a
moclobemide derivative or a moclobemide composition to a
human who in need of treatment for a somatised symptom. In a
preferred embodiment the human is not clinically depressed or
is subclinically depressed. Such method may be useful for
preventing the onset of depression or AD. The somatised
symptoms can be selected from the group consisting of lack of
energy, fatigue, muscular aches and pains or a symptom that
occurs in a somatoform disorder such as nausea, impaired
coordination/balance, paralysis, blindness, deafness,
seizures, dissociative symptoms, loss of consciousness and
pain during sexual intercourse, menstruation or urination.
Another object of this invention is to provide a
method for treating or preventing an illness selected from
the group consisting of a learning disability, conduct
disorder, oppositional defiant disorder, or a conduct
disturbance, in a human who is in need of treatment for said
illness and who does not suffer from attention deficit
hyperactivity disorder, comprising the step of administering
moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition. The invention also
provides a method for treating a conduct disturbance
comprising the step of administering moclobemide, a
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moclobemide metabolite, a moclobemide derivative or a
moclobemide composition to a human in need of treatment for a
conduct disturbance. Said conduct disturbance can be
selected from the group consisting of aggressive conduct;
causes or threatens physical harm to humans or animals; non-
agressive conduct that causes property loss or damage;
deceitfulness or theft; serious violations of rules; and
negativistic, defiant, disobedient, and hostile behavior
toward authority figures.
l0 Further, the present invention encompasses the use
of moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition to treat patients who
are immunocompromised or immunosupressed.
Moclobemide, as well as certain other moclobemide
derivatives, can be synthesized according to the method
described in United States Patent No. 4,210,754 to Burkard et
al., and in United States Patent No. 4,906,626 to Amrein et
al., which are incorporated by reference herein in their
entirety.
The moclobemide metabolite known as moclobemide-N-
oxide, which can be represented by the formula:
CI
C N CH2-CH2-Nip
U
has been shown to have MAO-A inhibitory activity, and its use
is also encompassed by the present invention.
Prodrugs, i.e. drugs that are metabolized in vivo
into the active agent, and methods for making prodrugs are
readily know in the art (e.g., Balant, L.P., ~~Prodrugs for
the Improvement of Drug Absorption Via Different Routes of
Administration,~~ Eur. J. Drucx Metab Pharmacokinet
15:143-153 (1990); and Bundgaard, H., ~~Novel Chemical
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Approaches in Prodrug Design," Druas of the Future 16:443-458
(1991); incorporated by reference herein). In one
embodiment, derivatives according to this invention have MAOI
activity.
The magnitude of a prophylactic or therapeutic dose
of the active ingredient (e. g., moclobemide, a moclobemide
metabolite, a moclobemide derivative) in accordance with the
present invention will vary with the severity of the
patient's affliction and the route of administration. The
dose and dose frequency will also vary according to the age,
weight and response of the individual patient. In general,
the recommended daily dose range for the conditions described
herein lies within the range of from about 50 mg to about
1200 mg per day, generally divided equally into doses given
one to four times a day. Preferably, a daily dose range
should be between 150 mg and 900 mg per day, usually divided
equally into a two to four times a day dosing. Most
preferably, a daily dose range should be between 150 mg and
600 mg per day, usually divided equally into a two to four
times a day dosing. It may be necessary to use dosages
outside these ranges in some cases, and the treating
physician will know how to increase, decrease or interrupt
treatment based upon patient response. The various terms
described above such as "therapeutically effective amount,"
are encompassed by the above-described dosage amounts and
dose frequency schedule.
For use in accordance with the present invention,
the treating physician will generally prescribe the period of
treatment and frequency of dose of moclobemide, a moclobemide
metabolite, a moclobemide derivative or a moclobemide
composition on a patient-by-patient basis. In general,
however, treatment with moclobemide, a moclobemide
metabolite, a moclobemide derivative or a moclobemide
composition may be carried out for as long a period as
necessary, either in a single, uninterrupted session, as is
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preferred for LAD, adolescent depression, RD, and RAD, or in
discrete sessions timed to coincide with exposure to
biochemical or hormonal stimuli likely to trigger symptoms,
as is preferred for treating the symptoms commonly associated
with AD, in the absence of depression. Most preferably,
moclobemide, a moclobemide metabolite, or a moclobemide
derivative therapy may be carried out for a period of at
least 4 weeks.
When used for treating or preventing LAD,
adolescent depression, or the symptoms commonly associated
with depression or AD in patients who do not have depression
or AD by DSM-IV criteria, moclobemide, a moclobemide
metabolite, a moclobemide derivative or a moclobemide
composition may be administered before, along with, or after
psychoactive compounds without antidepressant activity, such
as lithium.
Moclobemide, a moclobemide metabolite, a
moclobemide derivative or a moclobemide composition may also
be administered before, along with, or after traditional
psychotherapy. Thus, moclobemide, a moclobemide metabolite,
a moclobemide derivative or a moclobemide composition may be
utilized in accordance with the present invention as an
adjunct to conventional behavioral therapy that aims to
eliminate, minimize, or prevent depressive symptoms commonly
associated with the above-described disorders.
Any suitable route of administration may be
employed for providing the patient with an effective dosage
of moclobemide, a moclobemide metabolite, a moclobemide
derivative or a moclobemide composition. For example, oral,
rectal, parenteral, transdermal, subcutaneous, sublingual,
intranasal, intramuscular, intrathecal and the like may be
employed as appropriate. Dosage forms include tablets,
coated tablets, caplets, capsules (e. g. hard gelatin
capsules), troches, dragees, dispersions, suspensions,
solutions, patches and the like, including sustained release
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formulations well known in the art. See, e.g.~Introduction
to Pharmaceutical Dosage Forms, 1985, Ansel, H.C., Lea and
Febiger, Philadelphia, PA; Remington's Pharmaceutical
Sciences, 1995, Mack Publ. Co., Easton, PA.
The compositions of the present invention may also
comprise other therapeutic ingredients. The term
"pharmaceutically acceptable salt" refers to salts prepared
from pharmaceutically acceptable non-toxic acids including
inorganic acids and organic acids.
IO Since the compound of the present invention is
basic, salts may be prepared from pharmaceutically acceptable
non-toxic acids including inorganic and organic acids. Such
acids include malefic, acetic, benzene-sulfonic (besylate),
benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric,
gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric,
tartaric, p-toluenesulfonic acid and the like. Particularly
preferred are hydrobromic, hydrochloric, malefic, phosphoric,
and sulfuric acids.
The compositions include compositions suitable for
oral, rectal, transdermal, sublingual, and parenteral
administration (including subcutaneous, intramuscular,
intrathecal and intravenous), although the most suitable
route in any given case will depend on the nature and
severity of the condition being treated. The most preferred
route of administration of the present invention is the oral
route. The composition may be conveniently presented in unit
dosage form and prepared by any of the methods well-known in
the art of pharmacy.
In the case where an oral composition is employed,
a suitable dosage range for use is, e.g., from about 50 mg to
about 1200 mg per day, generally divided equally into a one
to four times a day dosing, preferably from about 150 mg to
about 900 mg per day, generally divided equally into a two to
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four times a day dosing and most preferably from about 150 mg
to about 600 mg per day, generally divided equally into a two
to four times a day dosing. Patients may be upward titrated
from below to within this dose range to achieve satisfactory
control or prevention of symptoms as appropriate.
In practical use, moclobemide, a moclobemide
metabolite, or a moclobemide derivative can be combined as
the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional
l0 pharmaceutical compounding techniques. The carrier may take
a wide variety of forms depending on the form of preparation
desired for administration, e.g., oral or parenteral
(including intravenous injections or infusions). In
preparing the compositions for oral dosage form, any of the
usual pharmaceutical media may be employed, for example,
water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like in the case of
oral liquid preparations, for example, suspensions, elixirs
and solutions; or aerosols; or carriers such as starches,
sugars, microcrystalline cellulose, stabilizers, diluents,
granulating agents, lubricants, binders, fillers,
disintegrating agents and the like in the case of oral solid
preparations such as, powders, capsules and tablets, with the
solid oral preparations being preferred over the liquid
preparations. The preferred solid oral preparation is
tablets. The most preferred solid oral preparation is coated
tablets. Because of their ease of administration tablets and
capsules represent the most advantageous oral dosage unit
form, in which case solid pharmaceutical carriers are
obviously employed. If desired, tablets may be coated by
standard aqueous or nonaqueous techniques. The preparation
of coated tablets, sachets, and hard gelatin capsules
containing moclobemide as the active ingredient is described
in United States Patent No. 4,906,626, which is incorporated
herein by reference.
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In addition to the common dosage forms set out
above, the compounds of the present invention may also be
administered by controlled release or sustained release means
and/or delivery devices such as those described in U.S.
Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;
3,630,200, 4,008,719, 4,687,660, and 4,769,027, the
disclosures of which are hereby incorporated by reference.
Preferred controlled release or sustained release tablets
suitable for use with moclobemide are described in U.S.
Patent No. 5,427,798, which is incorporated herein by
reference.
Pharmaceutical stabilizers may also be used to
stabilize compositions containing moclobemide or salts
thereof; acceptable stabilizers include but are not limited
to L-cysteine hydrochloride, glycine hydrochloride, malic
acid, sodium metabisulfite, citric acid, tartaric acid and L-
cysteine dihydrochloride. See, e.g. U.S. Patent No.
5,358,970, which is incorporated herein by reference.
Compositions of the present invention suitable for
oral administration may be presented as discrete units such
as capsules, cachets, or tablets or aerosol sprays, each
containing a predetermined amount of the active ingredient,
as a powder or granules or as a solution or a suspension in
an aqueous liquid, a non-aqueous liquid, an oil-in-water
emulsion, or a water-in-oil liquid emulsion. Such
compositions may be prepared by any of the methods of
pharmacy but all methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more necessary ingredients. In general,
the compositions are prepared by uniformly and intimately
admixing the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary,
shaping the product into the desired presentation. For
example, a tablet may be prepared by compression or molding,
optionally with one or more accessory ingredients.
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Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form
such as powder or granules, optionally mixed with one or more
of a binder, filler, stabilizer, lubricant, inert diluent,
and/or surface active or dispersing agent. Molded tablets
may be made by molding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent.
Desirably, each tablet contains from about 50 mg to about 300
mg of the active ingredient, and each cachet or capsule
contains from about 50 mg to about 300 mg of the active
ingredient. In a preferred embodiment, the tablet, cachet or
capsule contains one of four dosages: about 50 mg, about
75 mg, about 100 mg, and about 150 mg of active ingredient.
The invention is further defined by reference to
the following examples describing in detail the preparation
of the compound and compositions of the present invention.
It will be apparent to those skilled in the art that many
modifications, both to materials and to methods, may be
practiced without departing from the purpose and interest of
this invention.
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6. EXAMPLES
6.1. EXAMPLE 1
ORAL FORMULATION
Coated Tablets:
Formula Quantity per Tablet (mg.)
moclobemide 50.0
Lactose 74.0
Corn Starch 35.0
Water (per thousand Tablets) 30.0 ml
Magnesium Stearate 1.0
Corn Starch 25.0
The water evaporates during manufacture.
The active ingredient (moclobemide) is blended with
the lactose until a uniform blend is formed. The smaller
quantity of corn starch is blended with a suitable quantity
of water to form a corn starch paste. This is then mixed
with said uniform blend until a uniform wet mass is formed.
The remaining corn starch is added to the resulting wet mass
and mixed until uniform granules are obtained. The granules
are then screened through a suitable milling machine, using a
1/4 inch stainless steel screen. The milled granules are
then dried in a suitable drying oven until the desired
moisture content is obtained. The dried granules are then
milled through a suitable milling machine using 1/4 mesh
stainless steel screen. The magnesium stearate is then
blended and the resulting mixture is compressed into tablets
of desired shape, thickness, hardness and disintegration.
Tablets are coated by standard aqueous or
nonaqueous techniques. For example, 2.5 mg of
hydroxypropymethylcellulose can be dissolved in 25 mg of
deionized water. An aqueous (10 mg) suspension of 1.88 mg
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talc, 0.5 mg of titanium dioxide, 0.1 mg of yellow iron
oxide, and 0.02 mg of red iron oxide is stirred into this
solution. The coating suspension is sprayed on the tablets
and the coated tablets are dried overnight at 45aC.
6.2. EXAMPLE 2
ORAL FORMULATION
Capsules:
Formula Quantity per capsule in mg.
A B C
Active ingredient
moclobemide 25 50 75
Lactose 149.5 124.5 374
Corn Starch 25 25 50
Magnesium Stearate 0.5 0.5 1.0
Compression Weight 200.0 200.0 500.0
The active ingredient (moclobemide), lactose, and
corn starch are blended until uniform; then the magnesium
stearate is blended into the resulting powder. The resulting
mixture is encapsulated into suitably sized two-piece hard
gelatin capsules.
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6.3. EXAMPLE 3
ORAL FORMULATION
Tablets
Formula Quantity per Tablet in mg.
A_ _B _C
Active ingredient,
moclobemide 20 40 100
lactose BP 134.5 114.5 309.0
starch BP 30.0 30.0 60.0
Pre-gelatinized
Maize Starch BP 15.0 15.0 30.0
magnesium stearate 0.5 0.5 1.0
Compression Weight 200.0 200.0 500.0
The active ingredient (moclobemide) is sieved
through a suitable sieve and blended with lactose, starch,
and pre-gelatinized maize starch. Suitable volumes of
purified water are added and the powders are granulated.
After drying, the granules are screened and blended with the
magnesium stearate. The granules are then compressed into
tablets using punches.
Tablets of other strengths may be prepared by
altering the ratio of active ingredient to lactose or the
compression weight and using punches to suit. In particular,
single unit dosage forms of moclobemide in 50, 100, 150, and
200 mg are preferred and can be easily manufactured by those
of skill in the art. For example, tablets of the following
composition, as described in U.S. Patent No. 4,210,754,
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incorporated herein in its entirety, may be prepared by
methods known to those of skill in the art:
Tablets
Formula Quantity per Tablet in mg.
Active ingredient,
moclobemide 50.0
Lactose 95.0
Maize starch 100.0
Talc 4.5
Magnesium stearate 0.5
Weight per tablet 250.0
The embodiments of the present invention described above
are intended to be merely exemplary and those skilled in the
art will recognize, or be able to ascertain using no more
than routine experimentation, numerous equivalents to the
specific procedures described herein. All such equivalents
are considered to be within the scope of the present
invention and are covered by the following claims.
The contents of all references described herein are
hereby incorporated by reference. Throughout this
specification and claims, the word "comprise," or variations
such as "comprises" or "comprising," will be understood to
imply the inclusion of a stated integer or group of integers
but not the exclusion of any other integer or group of
integers.
Other embodiments are within the following claims.
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