U.S. patent application number 11/052533 was filed with the patent office on 2005-12-01 for omega-3 fatty acids in the treatment of depression.
Invention is credited to Stoll, Andrew.
Application Number | 20050267212 11/052533 |
Document ID | / |
Family ID | 27765310 |
Filed Date | 2005-12-01 |
United States Patent
Application |
20050267212 |
Kind Code |
A1 |
Stoll, Andrew |
December 1, 2005 |
Omega-3 fatty acids in the treatment of depression
Abstract
The present invention is directed to a method of treating
patients with major depression by administering omega-3 fatty
acids. These may be administered in a substantially purified form,
as part of a pharmaceutical composition, or as part of a larger
molecule, e.g., a triacylglycerol, which releases free fatty acid
after ingestion by a patient. The present invention is also
directed to triacylglycerols which are esterified at the gamma
cardon of glycerol to phosphocholine and at either the alpha or
beta carbon of glycerol to an omega-3 fatty acid. These "omega-3
phoshatidylcholines" are also used in the treatment of patients
with major depression.
Inventors: |
Stoll, Andrew; (Belmont,
MA) |
Correspondence
Address: |
CHOATE, HALL & STEWART LLP
TWO INTERNATIONAL PLACE
BOSTON
MA
02110
US
|
Family ID: |
27765310 |
Appl. No.: |
11/052533 |
Filed: |
February 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11052533 |
Feb 7, 2005 |
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10083913 |
Feb 27, 2002 |
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6852870 |
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10083913 |
Feb 27, 2002 |
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10068035 |
Feb 5, 2002 |
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10068035 |
Feb 5, 2002 |
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09269361 |
Mar 22, 1999 |
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6344482 |
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09269361 |
Mar 22, 1999 |
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PCT/US97/06712 |
Apr 23, 1997 |
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Current U.S.
Class: |
514/560 ;
514/221; 554/76 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/685 20130101;
A61K 31/5513 20130101; A61K 31/00 20130101; A61K 31/685 20130101;
A61K 33/00 20130101; A61K 31/202 20130101; A61P 25/24 20180101;
A61K 45/06 20130101; A61K 31/202 20130101; A61K 33/00 20130101 |
Class at
Publication: |
514/560 ;
554/076; 514/221 |
International
Class: |
A61K 031/202; A61K
031/5513 |
Claims
What is claimed is:
1. A method of treating a human patient for unipolar major
depression, comprising administering an omega-3 fatty acid to said
patient at a dosage sufficient to reduce or eliminate the symptoms
of unipolar major depression.
2. The method of claim 1, wherein said omega-3 fatty acid is
administered at a dose of between about 1 and about 30 grams per
day.
3. The method of claim 1, wherein said omega-3 fatty acid is in a
substantially pure form.
4. The method of claim 1, wherein said omega-3 fatty acid is
eicosapentanoic acid.
5. The method of claim 4, wherein said eicosapentanoic acid is
administered at a dose of between about 2 and about 10 grams per
day.
6. The method of claim 1, wherein said omega-3 fatty acid is
docosahexanoic acid.
7. The method of claim 6, wherein said docosahexanoic acid is
administered at a dose of between about 1 and about 5 grams per
day.
8. The method of claim 1, wherein said omega-3 fatty acid is
alpha-linolenic acid.
9. The method of claim 1, further comprising administering a
pharmaceutically effective dose of at least one member of lithium,
a pharmaceutical antidepressant, an herbal antidepressant, an
anticonvulsant, a mood stabilizer, an antipsychotic agent, and a
benzodiazepine.
10-20. (canceled)
21. A kit comprising a carrier containing in close confinement
therein one or more components, wherein: a) a first component
contains an omega-3 fatty acid; and b) a second component contains
a psychotropic medication useful in the treatment of unipolar major
depression.
22. The kit of claim 21 wherein: a) said first component contains
an omega-3 fatty acid selected from the group consisting of
eicosapentanoic acid, docosahexanoic acid, and alpha-linolenic
acid; and b) said second component is selected from the group
consisting of lithium, pharmaceutical antidepressant, an herbal
antidepressant, an anticonvulsant, a mood stabilizer, an
antipsychotic agent, and a benzodiazepine.
23-27. (canceled)
Description
[0001] This application is a continuation-in-part U.S. patent
application entitled "Omega-3 Fatty Acids and Omega-3
Phosphatidylcholine in the Treatment of Bipolar Disorder", filed
Feb. 5, 2002, using Express Mail No.: ET796587916US, which is a
continuation of U.S. Ser. No. 09/269,361, filed Mar. 22, 1999, now
issued as U.S. Pat. No. 6,344,482, which claims priority from
PCT/US97/06712, filed Apr. 23, 1997. The contents of all of these
applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to medical treatments for
psychiatric disorders. More specifically, it is concerned with
novel methods and compositions for treating patients with unipolar
major depression.
BACKGROUND OF THE INVENTION
[0003] Major depression is a neuropsychiatric illness characterized
by a persistently low mood or diminished interests in one's
surroundings, accompanied by at least several of the following
symptoms: Reduced energy and motivation, difficulty concentrating,
altered sleep and appetite, and at times, suicidal ideation
(American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, ed. 4. Washington, American Psychiatric
Association, 1994). Major depression without a history of
abnormally elevated mood and energy (mania) is termed "unipolar
major depression." However, a sizeable proportion of depressed
patients presenting for treatment have bipolar disorder (also known
as manic depressive illness), where there is a history of mania, or
a milder form of mood elevation known as hypomania (Goodwin F K,
Jamison K R: Manic Depressive Illness. London, Oxford University
Press, 1990). Whether part of a unipolar or a bipolar illness,
major depression is associated with high rates of morbidity and
mortality, with suicide rates of 10-25% (Kaplan H I, Sadock B J
(eds): Synopsis of Psychiatry. Baltimore, Williams & Wilkins,
1998, p. 866). According to the World Health Organization (WHO),
major depression is the fourth leading cause of World Health
Organization (WHO), major depression is the fourth leading cause of
vocational disability on earth (Murray C J L, Lopez A D (eds): The
Global Burden of Disease. Geneva, World Health Organization, 1996,
vol. 1). Furthermore, the incidence of major depression increased
and the age of onset of depression decreased with each passing
decade of the 20th century (Klerman G L, Weissman M M: Increasing
rates of depression. JAMA 1989; 261:2229-2235). Effective
psychotherapeutic and pharmacological antidepressant treatments for
major depression exist, but each has shortcomings. Two modern forms
of psychotherapy, cognitive-behavioral therapy and interpersonal
therapy, have shown efficacy in controlled studies of major
depression (Kaplan, 1998, pp. 885-931). However, for moderate or
severe depression, antidepressant medication is generally more
effective, rapidly acting, and less expensive than psychotherapy.
The combination of psychotherapy and medications has recently been
shown to be superior to either treatment modality (Keller M B, et
al.: A comparison of nefazodone, the cognitive behavioral-analysis
system of psychotherapy, and their combination for the treatment of
chronic depression. N Engl J Med 2000; 342:1462-1470). There are
more than 20 approved antidepressant drugs available in the United
States. All of these medications have proven acute efficacy for
major depression. The newer agents, such as the selective serotonin
reuptake inhibitors (SSRIs), are far less toxic than the older
classes of antidepressants, but even the SSRIs carry a substantial
burden of side-effects, including sexual dysfunction, sleep
disturbance, and weight gain (Kaplan, 1998). In addition, no
currently available antidepressant is acutely effective in more
than 60-70% of the patients who receive it. Furthermore, long-term
data exists for only a few antidepressant drugs, and it appears
that efficacy may diminish over time with some agents (Fredman S J,
et al.: Partial response, nonresponse, and relapse with selective
serotonin reuptake inhibitors in major depression: a survey of
current "next-step" practices. J Clin Psychiatry; 2000,
61:403-408). Thus, there is a need for newer treatments, with
greater efficacy and safety, as well as fewer side-effects.
SUMMARY OF THE INVENTION
[0004] A method has been developed for treating a human patient for
unipolar major depression by administering omega-3 fatty acids at a
dosage sufficient to reduce or eliminate its symptoms, i.e. at a
dosage sufficient to reduce the frequency or lessen the severity of
depression experienced by such patients. The most preferred omega-3
fatty acids are eicosapentanoic acid, docosahexanoic acid, and
.alpha.-linolenic acid. The fatty acids may be administered as the
sole therapeutic agent or in conjunction with other agents known to
be useful in the treatment of depression in patients. In
particular, the fatty acids may be administered with an additional
psychotropic medication. In addition, omega-3 fatty acids may be
taken by patients as a component of another molecule, e.g. a
triacylglycerol, and be metabolically released after ingestion.
[0005] The present invention is also directed to an omega-3
phosphatidylcholine useful in the treatment of unipolar major
depression, consisting of glycerol esterified at both its .alpha.
and .beta. carbons to fatty acids. At least one, and preferably
both, of these fatty acids is an omega-3 fatty acid, and the
position of the glycerol should be esterified to phosphocholine. It
is preferred that at least one of the esterified fatty acids be
eicosapentanoic acid, docosahexanoic acid, or .alpha.-linolenic
acid. Omega-3 phosphatidylcholines with eicosapentanoic acid
esterified to the carbon and docosahexanoic acid esterified to the
.beta. carbon, or vice versa, are the most preferred. In all cases,
the position of the triacylglycerol is esterified to
phosphocholine.
DETAILED DESCRIPTION OF THE INVENTION
[0006] In the following description, reference will be made to
various methodologies well-known to those skilled in the art of
medicine and pharmacology. Such methodologies are described in
standard reference works setting forth the general principals of
these disciplines. Included among the relevant references are:
Goodwin, F. K. and Jamison, K. R., Manic Depressive Illness, Oxford
University Press (1990); and Bloom, F. and Kupfer, D.,
Psychopharmacology. The Fourth Generation of Progress, Raven Press
(1994).
[0007] A. Definitions
[0008] Major Depression: Major depression is characterized by two
or more weeks of predominantly low mood or diminished interest in
one's usual activities combined with four or more of the following
symptoms: sleep alteration (either increased or decreased),
inappropriate guilt or loss of self-esteem, altered appetite
(either incresed or decreased), diminished energy, diminished
concentration, psychomotor symptoms (either agitation or
retardation), and suicidal ideation.
[0009] Omega-3 fatty acids: Fatty acids are long chain
polyunsaturated molecules beginning with a methyl group and ending
with a carboxyl group. Omega-3 fatty acids contain a double bond in
the third position from the methyl group. Two common, long chain
omega-3 fatty acids are eicosapentanoic acid (20 carbons in length)
and docosahexanoic acid (22 carbons in length). These are both
found in fish oils
[0010] Triacylglycerol: Compounds in which the carboxyl groups of
fatty acids are esterified to the hydroxyls of all three carbons
found in glycerol are referred to as triacylglycerols or
triglycerides. Triacylglycerols in which the terminal carbon of
glycerol (the ".gamma. carbon") is esterified to phosphocholine are
called phosphatidylcholines. The next carbon in the glycerol is
referred to herein as the ".beta. carbon," and the following carbon
is referred to as the ".beta. carbon."
[0011] Omega-3 phosphatidylcholine: As used herein the term
"omega-3 phosphatidylcholine" refers to a triacylglycerol in which
the .gamma. carbon of glycerol is esterified to phosphocholine, and
at least one of the other carbons of glycerol is esterified to an
omega-3 fatty acid.
[0012] Choline: Choline (hydroxyethyl trimethyl ammonium hydroxide)
is considered to be a vitamin of the B complex and is derivable
from many foods. Unless otherwise indicated, the term "choline" as
used herein, refers not only to the isolated choline molecule (i.e.
free choline) but also to any biologically compatible salt of
choline (e.g., choline bitartrate).
[0013] Lithium: Unless otherwise indicated, the term "lithium"
refers to any salt containing lithium as the cationic
component.
[0014] Unipolar Major Depression: Unipolar major depression is a
mood disorder in which patients suffer from one or more episodes of
major depression.
[0015] B. Background
[0016] Omega-3 fatty acids have been linked to the etiology,
pathophysiology, and treatment of unipolar major depression. Six
lines of evidence support a role for the omega-3 fatty acids in
major depression. First, there are compelling epidemiological
hypotheses and data linking low omega-3 fatty acid intake with high
rates of major depression (Smith R S: The macrophage theory of
depression. Med Hypotheses; 1991, 35:298-306; Rudin D O: The major
psychoses and neuroses as omega-3 essential fatty acid deficiency
syndrome: substrate pellagra. Biol Psychiatry; 1981, 16:837-850;
Hibbeln J R, Salem N: Dietary polyunsaturated fats and depression:
when cholesterol does not satisfy. Am J Clin Nutr; 1995, 62:1-9;
Hibbeln J R: Fish consumption and major depression. Lancet; 1998,
351:1213). For example, Hibbeln reported his findings of a very
strong relationship between the per capita amount of fish a given
country consumes and the rates of major depression within that
country (Hibbeln, 1998). The second and third lines of evidence
involve neurochemical studies of omega-3 fatty acid function in
animals and biochemical analyses of the omega-3 content of blood of
patients with major depression, respectively (Delion S, et al.:
Alpha-Linolenic acid dietary deficiency alters age-related changes
of dopaminergic and serotonergic neurotransmission in the rat
frontal cortex. J Neurochem; 1996, 66(4):1582-91; Chalon S, et al.:
Dietary fish oil affects monoaminergic neurotransmission and
behavior in rats. J Nutr 1998; 128(2):2512-9; Heron D S, et al.:
Lipid fluidity markedly modulates the binding of serotonin to mouse
brain membranes. Proc Natl Acad Sci, USA; 1980, 77:7463-7467; Adams
P B, et al.: Arachadonic acid to eicosapentaenoic acid ratio in
blood correlates positively with clinical symptoms of depression.
Lipids; 1996, 31 suppl: S157-S161; Maes M, et al.: Fatty acid
composition in major depression: decreased omega-3 fractions in
cholesteryl esters and increased C20:4 omega 6/C20:5 omega 3 ratio
in cholysteryl esters and phospholipids. J Affect Disord; 1996,
38:35-46; Peet M, et al.: Omega-3 polyunsaturated fatty acid levels
in the diet and in red blood cell membranes of depressed patients.
J Aff Disorders; 1998, 48:149-55). The omega-3 fatty acids have
fundamental structural and functional roles in the developing and
mature nervous system (Uauy R, et al.: Role of essential fatty
acids in the function of the developing nervous system. Lipids;
1996, 31:S167-S176; Bourre J M, et al.: Function of dietary
polyunsaturated fatty acids in the nervous system. Prostaglandins
Leukotrienes and Essential Fatty Acids; 1993, 48: 5-15). The fourth
line of evidence points to the presence of abnormalities in the EPA
dependant eicosanoid and cytokine pathways in the brain during
major depression (Smith, R S, 1991; Maes M, et al.: Significantly
increases expression of T-cell activation markers (interleukin-2
and HLA-DR) in depression: further evidence for an inflammatory
process during that illness. Prog Neuropsychopharmacol Biol
Psychiat; 1993, 17:241-255; Maes M: Evidence for an immune response
in major depression: a review and hypotheses. Prog
Neuropsychopharmacol & Biol Psychiat; 1995, 19:11-38). The
fifth line of evidence is the strong antidepressant effect of the
omega-3 fatty acids observed a recent double-blind,
placebo-controlled study in bipolar disorder (Stoll A L, et al.:
Omega-3 fatty acids in bipolar disorder: a preliminary
double-blind, placebo-controlled trial. Archives Gen Psychiatry;
1999, 56:407-412). This study is relevant because all compounds
with antidepressant effects in bipolar disorder will exhibit
antidepressant effects in unipolar depression. The final line of
evidence involves preliminary uncontrolled open-label clinical
studies reporting mood elevating effects of the omega-3 fatty acids
in patients with unipolar depression and other neuropsychiatric
disorders (Rudin, 1981; Stoll A L, et al.: Omega-3 fatty acids and
bipolar disorder: a review. Prostaglandins, Leukotrienes, and
Essential Fatty Acids; 1999, 60:329-37).
[0017] Omega-6 fatty acids (particularly arachidonic acid, or AA)
are generally antagonistic to omega-3 (EPA) action in the immune
and inflammatory systems (Lands WEM: Biochemistry and physiology of
n-3 fatty acids. FASEB J; 1992, 6:2530-2536). Unlike omega-3 fatty
acids, omega-6 fatty acids are ubiquitous in developed countries.
Omega-6 fatty acids are derived from seed and vegetable oils that
have increased in our diet through the incorporation of these oils
by the food industry--at the recommendation of the American Heart
Association and others (Report of the Dietary Guidelines Advisory
Committee on the Dietary Guidelines for Americans. In: Dietary
Guidelines for Americans; Washington, D.C. US Dept of Health and
Human Services; 2000). There is indirect evidence that the optimal
dietary ratio of omega-6 to omega-3 fatty acids should be close to
1:1, and under these optimal conditions, the omega-6 fatty acid AA
competes with the omega-3 fatty acid EPA to achieve balanced immune
and inflammatory function (Leaf A, Weber P C: A new era for science
in nutrition. Am J Clin Nutr; 1987, 45:1048-1053; Eaton S B:
Humans, lipids and evolution. Lipids; 1992, 27:814-820; Simopoulos
A P, et al.: Workshop on the essentiality of an recommended dietary
intakes for omega-6 and omega-3 fatty acids. J Am Coll Nutr; 1999,
18:487-489, Lands, 1992). Like EPA, AA is converted to a series of
eicosanoids, including the prostaglandins and leukotrienes, which
have an important role in regulating leukocyte cytokine production
and release. Landes has reported that the eicosanoids from
arachidonic acid are synthesized in an intense and rapid manner,
and likewise have intense and powerful actions in the body (Lands,
1992). Eicosanoids derived from the omega-3 fatty acid EPA are
created more slowly and their actions are often moderate in
comparison to the omega-6 derived eicosanoids. EPA and AA are
intended to be in balance, and without sufficient EPA, AA and its
progeny will monopolize eicosanoid-associated systems throughout
the body, increasing the risk for intense, unchecked inflammatory
responses. Such an imbalance towards the omega-6 eicosanoids causes
white blood cells to release potent immune activating cytokines,
which can adversely affect health if chronically or abnormally
activated. Likewise, EPA can dramatically check this AA driven
process at several levels, including direct inhibition of the
eicosanoid producing enzyme cyclooxygenase-2 (Obata T, et al.:
Eicosapentaenoic acid inhibits prostaglandin D2 generation by
inhibiting cyclo-oxygenase-2 in cultured human nast cells. Clin Exp
Allergy; 1999, 2:1129-1135).
[0018] In collaboration with Baylor College of Medicine, a 2-site
study designed to examine the efficacy of omega-3 fatty acids in
patients with unstable bipolar disorder was performed (Stoll,
1999). The study was performed to confirm the hypothesis that one
could discover new mood agents by searching the medical literature
for compounds with biochemical actions similar to currently used
medications. The omega-3 fatty acids shared characteristics with
lithium, valproate, and even the SSRI class of antidepressants.
This pilot study was a 4-month, prospective, double-blind, parallel
design, placebo-controlled trial, comparing the efficacy of high
dose omega-3 fatty acids from fish oil (9.6 grams per day) vs.
placebo (olive oil) in bipolar patients who had experienced a
recent mania or hypomania.
[0019] The study was originally intended to run 9 months per
patient. However, the study was terminated after a pre-planned
interim data analysis at the 4-month mark revealed marked
differences between the omega-3 fatty acid and placebo groups. In
nearly every outcome measure, the omega-3 fatty acid group
performed better than the placebo group. Nine of 14 (64.3%)
patients treated with omega-3 fatty acids responded to treatment,
compared to 3 of 16 (18.8%) placebo-treated subjects (p=0.02;
Fisher). The omega-3 fatty acids in this study demonstrated mood
stabilizing activity. However, the most robust finding was the
strong antidepressant effects of the omega-3 fatty acids in this
group of bipolar patients.
[0020] In 1981, Rudin, published an open-label case-series on the
use of high dosages of flaxseed oil in psychiatric patients with a
variety of diagnoses (Rudin, 1981). He noted antidepressant
effects, as well as a frequent occurrence of mania, presumably
induced by the large dosage of .alpha.-linolenic acid used. In
terms of other uncontrolled data, the authors have previously
described treating 16 patients with treatment-refractory unipolar
major depression with omega-3 fatty acids (Stoll, 1999). Five of
the 16 patients responded at least partially, while 4 of the 5
responders had a marked response to the addition of omega-3 oils to
their ongoing antidepressant treatment. Although 5 of 16 (31%) may
seem like a low rate of response to a treatment, it is important to
keep in mind that patients with treatment-resistant depression
often have response rates well below this figure.
[0021] Several compelling and independent lines of evidence support
a role for the omega-3 fatty acids in the etiology, pathogenesis,
and the treatment of unipolar major depression. Historically, DHA
has been the major focus of many investigators due to its large
structural role in the brain. However, EPA is involved in a huge
array of neuropsychiatrically relevant biochemical processes, and
the bulk of the biochemical data in patients with unipolar
depression indicates that EPA depletion is more highly correlated
with depression severity than the other omega-3 fatty acids. There
are also preliminary indications that .alpha.-linolenic acid may
also possess antidepressant action.
[0022] C. Method of Treating Patients For Major Depression Using
Omega-3 Fatty Acids
[0023] The present invention is directed to a method for treating
human patients for unipolar major depression by administering
omega-3 fatty acids. Although the method is not restricted to any
one particular type of omega-3 fatty acid, it is preferred that
eicosapentanoic acid (EPA) or docosahexanoic acid (DHA) be used.
Both EPA and DHA are found in a variety of fish oils and are
commercially available in an essentially pure form.
[0024] Dosage
[0025] The total daily dosage of omega-3 fatty acid administered to
a human patient should be at least the amount required to reduce or
eliminate the symptoms associated with major depression.
Specifically, the dosage should be high enough to either reduce the
severity of the depressive episodes experienced by patients or
decrease the frequency at which such episodes occur. Physicians may
begin by administering relatively small doses of omega-3 fatty acid
(e.g. 1 gram per day) and then adjust the dosage upward as it
becomes clear that the patient can tolerate the treatment. The
final daily dosage should be between 1 and 30 grams of fatty acid
per day, with typical doses ranging between 2 and 10 grams per day.
Dosages may be provided in either a single or multiple dosage
regiment.
[0026] These are simply guidelines since the actual dose must be
carefully selected and titrated by the attending physician based
upon clinical factors unique to each patient. The optimal daily
dose will be determined by methods known in the art and will be
influenced by factors such as the age of the patient and other
clinically relevant factors. In many cases, a patient will already
be taking medications for the treatment of major depression at the
time that treatment with omega-3 fatty acid is initiated. In
addition, patients may be taking medications for other diseases or
conditions. The other medications may be continued during the time
that omega-3 fatty acid is given to the patient, but it is
particularly advisable in such cases to begin with low doses to
determine if adverse side effects are experienced.
[0027] Dosage Forms and Route of Administration
[0028] The present invention is not limited to any particular
dosage form or route of administration. Oral administration will
generally be most convenient; however, the invention is compatible
with parenteral, transdermal, sublingual, buccal or implantable
routes of administration as well.
[0029] Omega-3 fatty acids may be given in a substantially purified
form or as part of a pharmaceutical composition containing one or
more excipients or flavoring agents. Compositions may also include
psychotropic medications, including lithium, antidepressants,
anticonvulsants, mood stabilizers, antipsychotic agents, and
benzodiazepines. Preparations may be solid or liquid and take any
of the pharmaceutical forms presently used in human medicine, e.g.
tablets, gel capsules, granules, suppositories, transdermal
compositions or injectable preparations.
[0030] The active ingredient or ingredients may be incorporated
into dosage forms in conjunction with any of the vehicles which are
commonly employed in pharmaceutical preparations, e.g. talc, gum
arabic, lactose, starch, magnesium searate, cocoa butter, aqueous
or non-aqueous solvents, oils, paraffin derivatives or glycols.
Emulsions such as those described in U.S. PAT. No. 5,434,183, may
also be used in which vegetable oil (e.g., soybean oil or safflower
oil), emulsifying agent (e.g., egg yolk phospholipid) and water are
combined with glycerol. Fatty acids may be incorporated into
preparations either in the form of the free acid or as a
pharmaceutically acceptable salt. Methods for preparing appropriate
formulations are well known in the art (see e.g., Remington's
Pharmaceutical Sciences, 16th Ed., 1980, A. Oslo Ed., Easton,
Pa.).
[0031] Manner of Treatment
[0032] In order to determine the effect of administered omega-3
fatty acid on mood alteration, patients should be evaluated on a
regular basis over an extended period of time, e.g. 1 to 8 weeks.
One good manner of carrying out evaluations is for patients to keep
a daily diary in which they chart their moods. For example,
patients may keep a daily record in which they rate their best and
worst moods as either normal, mildly, moderately or severely
depressed. These records should help the patient and their
physician determine if depression occurs less frequently or becomes
less extreme in intensity. Ideally, such a diary should be kept
both before and after the administration of omega-3 fatty acid is
begun. The evaluation of mood alterations by the patient should
also be supplemented with periodic clinical evaluations carried out
by a physician.
[0033] In some cases, the evaluation discussed above may indicate
that mood fluctuations have become so stabilized in a patient as
the result of administering omega-3 fatty acid at the initial
concentration that no further adjustment in dosage is necessary. In
other cases, the dosage of omega-3 fatty acid may be increased in
order to obtain a more efficacious result. In general, dosage
should not be increased beyond the point at which further
stabilization of patient mood is observed. If adverse side effects
are experienced by patients, then dosages may be adjusted in a
downward direction accordingly.
[0034] The process of adjusting dosage in an upward or downward
direction and evaluating the effect of the adjustment on mood
changes should be continued until an optimum dosage is discovered,
i.e. the dosage at which the patient experiences the best balance
between therapeutic effectiveness and discomfort due to side
effects. In cases where adverse side effects are not experienced,
the optimal dosage is the lowest dose resulting in maximum
reduction in depressive episodes.
[0035] Omega-3 fatty acids may be used in combination with other
psychotropic agents including, for example, lithium, pharmaceutical
antidepressants, herbal antidepressants (e.g., St. John's Wort,
S-adenosylmethionine), anti-convulsants, mood stabilizers,
antipsychotic agents, and benzodiazepines. These other agents may
either be given together with omega-3 fatty acid in a single dosage
form, or they may be administered separately.
[0036] Patients taking anti-depressants should continue taking the
drug during the time at which omega-3 fatty acid treatment is
begun. Optimal dosages for each of the drugs may then be determined
sequentially. For example, administration of one agent may be
initiated and then optimized followed by the initiation and
optimization of omega-3 fatty acid treatment. The problem of
adjusting the dosages of multiple therapeutic agents is one that is
routinely encountered by physicians and can be solved using
well-established procedures similar to those discussed herein.
[0037] Kits
[0038] Individual preparations containing omega-3 fatty acid and
other therapeutic agents for major depression, such as choline or
lithium, may be provided in the form of a kit, comprising a carrier
(e.g. a box or bag) compartmentalized to receive one or more
components (bottles, vials, packets, etc.) in close confinement.
Such a kit will be carried by patients with major depression and
will typically contain written instructions concerning the way in
which the enclosed drugs should be taken, potential side effects,
etc. The kit should be portable, and be generally convenient for
use by patients.
[0039] D. Omega-3 Phosphatidyleholines
[0040] The present invention is also directed to omega-3
phosphatidylcholines in which glycerol is esterified at its .gamma.
carbon to phosphocholine and at least one of the fatty acids
esterified to either the .alpha. or .beta. carbons is an omega-3
fatty acid. It is preferred that both the .alpha. carbon and .beta.
carbon of glycerol be esterified to an omega-3 fatty acid, with the
preferred fatty acids being EPA and DHA. The most preferred
phosphatidylcholines contain both DHA and EPA, one esterified at
the a carbon of glycerol and the other at the .beta. carbon.
[0041] The phosphatidylcholines of the present invention may be
synthesized using standard techniques well known in the art, see
e.g. U.S. Pat. No. 4,701,468. One suitable method is to synthesize
the "omega-3 phosphatidylcholines" from commercially available
precursor lyso-phosphatidylcholines. Specifically, a
lyso-phosphatidylcholine is acylated by combining the desired
omega-3 fatty acid anhydride (e.g. from EPA or DHA) and
4-pyrrolidinopyridine as a catalyst (1.2 equivalents) in
alcohol-free chloroform. Depending on the reaction conditions and
the relative proportions of fatty acid, several different omega-3
phosphatidylcholine species will be generated. Using EPA and DHA,
four major species will occur:
dieicosapentanoylphosphatidylcholine,
didocosahexanoylphosphatidylcholine, 1-eicosapentanoyl,
2-docosahexanoylphosphatidylcholine, and 1-docosahexanoyl,
2-eicosapentanoylphosphatidylcholine. The specific
phosphatidylcholines of interest may then be isolated by
well-established chromatographic methods.
[0042] E. Method of Treating Bipolar Disorder Using Omega-3
Phosphatidylcholines
[0043] The omega-3 phosphatidylcholines described above may be used
for treating humans with unipolar major depression in the same
manner and following the same procedures as those discussed in
connection with omega-3 fatty acids. The phosphatidylcholines may
be given in a substantially purified form or as part of a
pharmaceutical composition. It is expected that optimized dosages
will have sufficient omega-3 phosphatidylcholine to deliver between
about one and about 30 grams of free omega-3 fatty acid per day,
with the preferred daily dose being between 1 and 10 grams.
Patients should keep diaries of daily mood fluctuations and be
evaluated by a physician on a regular basis to determine the effect
of treatment. Based upon such evaluations, dosages may be increased
or decreased as needed.
[0044] As with omega-3 fatty acids, the omega-3
phosphatidylcholines may be delivered by any route and are
compatible with any dosage form. Oral dosage forms such as tablets,
capsules, powder packets and liquid solutions will generally be
preferred. Therapeutically inert agents may be added to improve the
palatability of preparations, and additional therapeutic agents may
be included.
[0045] In cases where parenteral administration is elected as the
route of administration, preparations containing omega-3
phosphatidylcholine may be provided to patients in combination with
pharmaceutically acceptable sterile aqueous or non-aqueous
solvents, suspensions or emulsions. Examples of non-aqueous
solvents are propylene glycol, polyethylene glycol, vegetable oil,
fish oil, and injectable organic esters. Aqueous carriers include
water, water-alcohol solutions, emulsions or suspensions, including
saline and buffered medical parenteral vehicles including sodium
chloride solution, Ringer's dextrose solution, dextrose plus sodium
chloride solution, Ringer's solution containing lactose, or fixed
oils. Intravenous vehicles may include fluid and nutrient
replenishers, electrolyte replenishers, such as those based upon
Ringer's dextrose, and the like.
[0046] Omega-3 phosphatidylcholine and other psychotropic agents,
e.g., lithium, antidepressants, anticonvulsants, mood stabilizers,
antipsychotic agents, and beneodiazepines, may be provided as
separate components in the form of a kit designed to be carried and
used by patients. The kit would contain written instructions
concerning the way in which the enclosed agents should be taken and
other pertinent information.
[0047] All references cited herein are fully incorporated by
reference. Having now fully described the invention, it will be
understood by those of skill in the art that the invention may be
performed within a wide and equivalent range of conditions,
parameters and the like, without affecting the spirit or scope of
the invention or any embodiment thereof.
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