U.S. patent application number 15/417689 was filed with the patent office on 2017-06-29 for intranasal administration of ketamine to treat depression.
The applicant listed for this patent is Icahn School of Medicine at Mount Sinai, The USA, as represented by the Secretary, Department of Health and Human Services, The USA, as represented by the Secretary, Department of Health and Human Services, Yale University. Invention is credited to Dennis S. Charney, John H. Krystal, Husseini K. Manji, Sanjay J. Mathew, Carlos A. Zarate.
Application Number | 20170181966 15/417689 |
Document ID | / |
Family ID | 38541630 |
Filed Date | 2017-06-29 |
United States Patent
Application |
20170181966 |
Kind Code |
A1 |
Charney; Dennis S. ; et
al. |
June 29, 2017 |
INTRANASAL ADMINISTRATION OF KETAMINE TO TREAT DEPRESSION
Abstract
Methods and compositions for the treatment of
treatment-resistant depression are described. More specifically,
the invention demonstrates that intranasal administration of
ketamine is effective to ameliorate the symptoms of depression in a
patient who has not responded to an adequate trial of one
antidepressant in the current episode and has recurrent or chronic
depressive symptoms (>2 years).
Inventors: |
Charney; Dennis S.; (New
York, NY) ; Mathew; Sanjay J.; (New York, NY)
; Manji; Husseini K.; (Rockville, MD) ; Zarate;
Carlos A.; (Rockville, MD) ; Krystal; John H.;
(New Haven, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Icahn School of Medicine at Mount Sinai
Yale University
The USA, as represented by the Secretary, Department of Health and
Human Services |
New York
New Haven
Rockville |
NY
CT
MD |
US
US
US |
|
|
Family ID: |
38541630 |
Appl. No.: |
15/417689 |
Filed: |
January 27, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14306382 |
Jun 17, 2014 |
9592207 |
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15417689 |
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14197767 |
Mar 5, 2014 |
9539220 |
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14306382 |
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11688603 |
Mar 20, 2007 |
8785500 |
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14197767 |
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60785108 |
Mar 22, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 15/08 20130101;
A61M 15/0068 20140204; A61K 9/12 20130101; A61K 31/137 20130101;
A61K 45/06 20130101; A61P 25/24 20180101; A61K 9/008 20130101; A61K
9/7023 20130101; A61K 31/135 20130101; A61K 9/0019 20130101; A61K
9/0043 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 45/06 20060101 A61K045/06; A61K 9/70 20060101
A61K009/70; A61K 31/135 20060101 A61K031/135 |
Goverment Interests
[0002] This invention was made with government support under Grant
No. 1Z01MH002857-01 awarded by the National Institutes of Health,
and a Merit Review Grant from the Department of Veterans Affairs,
NIMH Program Grant. The government has certain rights in the
invention.
Claims
1. A method of treating a human patient afflicted with
treatment-resistant-depression, comprising intranasally
administering a metered dose of a composition comprising ketamine
and at least one pharmaceutically acceptable excipient to said
patient wherein the amount of ketamine in the metered dose is
sufficient to reduce or eliminate the symptoms of said
treatment-resistant depression.
2. The method of claim 1, wherein said ketamine is administered at
a dose of between about 0.1 mg/kg per day to about 3.0
mg/kg/day.
3. The method of claim 1, wherein the symptoms of said
treatment-resistant depression are alleviated within 2 hours of
intranasal administration of said ketamine.
4. The method of claim 1, wherein said method comprises intranasal
administration of a single dose of said ketamine.
5. The method of claim 1, wherein said method comprises intranasal
administration of multiple doses of said ketamine.
6. The method of claim 1, wherein a single intranasal
administration of said ketamine is sufficient to alleviate the
effects of said depression for 7 days.
7. The method of claim 1, further comprising administering a
pharmaceutically effective dose of a second agent, wherein said
second agent is an antidepressant agent.
8. The method of claim 7 wherein said antidepressant agent is
selected from the group consisting of at least one member of
lithium, a pharmaceutical antidepressant, an herbal antidepressant,
an anticonvulsant, a mood stabilizer, an antipsychotic agent, and a
benzodiazepine.
9. A kit comprising a carrier for delivering a medicament
intranasally containing in close confinement therein one or more
components, wherein: a) a first component contains ketamine; and b)
a second component contains a psychotropic medication useful in the
treatment of depression.
10. The kit of claim 9 wherein 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.
11. A device for patient self-administration of ketamine comprising
a nasal spray inhaler containing an aerosol spray formulation of
ketamine and a pharmaceutically acceptable dispersant, wherein the
device is metered to disperse an amount of the aerosol formulation
by forming a spray that contains a dose of ketamine effective to
alleviate depression but which dose of ketamine is determined by a
physician or medical care provider to be below a level that causes
dysphoria.
12. A method of treating a human patient afflicted with
treatment-resistant depression, comprising intravenously
administering multiple doses of a composition comprising ketamine
to said patient at a dosage sufficient to reduce or eliminate the
symptoms of said treatment-resistant depression.
13. The method of claim 12, wherein said ketamine is in a
pharmaceutically acceptable carrier and is administered at a dose
of between about 0.1 mg/kg per day to about 3.0 mg/kg/day.
14. The method of claim 12, wherein the symptoms of said
treatment-resistant depression are alleviated within two hours of
administration of said ketamine.
15. The method of claim 12, wherein the composition is administered
at least six times in fourteen days.
16.-21. (canceled)
22. The method of claim 12, wherein the composition is administered
at least nine times in 21 days.
23. The method of claim 12, further comprising administering a
pharmaceutically effective dose of a second agent, wherein said
second agent is an antidepressant agent.
24. The method of claim 23, wherein said antidepressant agent is
selected from the group consisting of at least one member of
lithium, a pharmaceutical antidepressant, an herbal antidepressant,
an anticonvulsant, a mood stabilizer, an antipsychotic agent, and a
benzodiazepine.
25. A method of treating a human patient afflicted with
treatment-resistant depression, comprising transdermally
administering a composition comprising ketamine to said patient at
a dosage sufficient to reduce or eliminate the symptoms of said
treatment-resistant depression.
26. The method of claim 25, wherein said ketamine is in a
pharmaceutically acceptable carrier and is administered at a dose
of between about 0.1 mg/kg per day to about 3.0 mg/kg/day.
27. The method of claim 25, wherein the symptoms of said
treatment-resistant depression are alleviated within two hours of
transdermal administration of said ketamine.
28. The method of claim 25, wherein said method comprises
transdermal administration of multiple doses of said ketamine.
29. The method of claim 25, further comprising administering a
pharmaceutically effective dose of a second agent, wherein said
second agent is an antidepressant agent.
30. The method of claim 25, wherein said antidepressant agent is
selected from the group consisting of at least one member of
lithium, a pharmaceutical antidepressant, an herbal antidepressant,
an anticonvulsant, a mood stabilizer, an antipsychotic agent, and a
benzodiazepine.
31. A device for patient self-administration of ketamine comprising
a transdermal patch containing a formulation of ketamine and a
pharmaceutically acceptable carrier, wherein the device is metered
to disperse an amount of the formulation that contains a dose of
ketamine effective to alleviate depression but which dose of
ketamine is determined by a physician or medical care provider to
be below a level that causes dysphoria.
32. The method of claim 1 wherein the pharmaceutically acceptable
excipient comprises a mucosal penetration enhancing agent.
33. The method of claim 1 wherein the pharmaceutically acceptable
excipient comprises a dispersing agent.
34. The method of claim 1 wherein the intranasal administration
comprises an aerosol spray.
35. The method of claim 33 wherein the pharmaceutically acceptable
excipient comprises a surfactant.
36. The method of claim 1 wherein the pharmaceutically acceptable
excipient comprises a propellant.
37. The method of claim 1 wherein said ketamine is administered at
a dose of between about 0.01 mg/kg per day to about 1.0
mg/kg/day.
38. The method of claim 34 wherein the aerosol spray comprises a
dry powder.
39. The method of claim 34 wherein the aerosol spray comprises a
liquid aerosol formulation.
40. The method of claim 1 wherein the treatment resistant
depression comprises dysthymia.
Description
[0001] The present application claims the benefit of priority of
U.S. Provisional Application No. 60/785,108, which was filed Mar.
22, 2006. The entire text of the aforementioned application is
incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to methods and compositions
for the treatment of depression. More particularly, the invention
relates to intranasal, intravenous and transdermal administration
of ketamine to treat treatment-resistant depression.
BACKGROUND OF THE INVENTION
[0004] Depression is among the most disabling of all medical
disorders with a lifetime prevalence of approximately 17% [1]. It
frequently appears early in life, can run a chronic course, and
adversely affect the prognosis of other medical illnesses, such as
coronary vascular disease, diabetes, and osteoporosis.
[0005] Depression is characterized by depressed mood, and markedly
diminished interest or pleasure in activities. Other symptoms
include significant weight loss or weight gain, decrease or
increase in appetite, insomnia or hypersomnia, psychomotor
agitation or retardation, fatigue or loss of energy, feelings of
worthlessness or excessive or inappropriate guilt, diminished
ability to think or concentrate or indecisiveness, recurrent
thoughts of death, suicidal ideation or suicidal attempts. A
variety of somatic symptoms may also be present. Though depressive
feelings are common, especially after experiencing setbacks in
life, depressive disorder is diagnosed only when the symptoms reach
a threshold and last at least two weeks. Depression can vary in
severity from mild to very severe. It is most often episodic but
can be recurrent or chronic. Some people have only a single
episode, with a full return to premorbid function. However, more
than 50 percent of those who initially suffer a single major
depressive episode eventually develop another.
[0006] Depression is more common in women than in men. The point
prevalence of unipolar depressive episodes is estimated to be 1.9%
for men and 3.2% for women, and 5.8% of men and 9.5% of women will
experience a depressive episode in a 12-month period. These
prevalence figures vary across populations and may be higher in
some populations. A World Health Organization study has reported
that depression is the leading global cause of years of life lived
with disability and the fourth leading cause of disability-adjusted
life-years. Disability-adjusted life-years refers to the reduction
in an individual's productive life, and is a measure that takes
into account premature mortality [2].
[0007] The treatment of depression was revolutionized about a
half-century ago by the serendipitous discovery of monoamine
oxidase inhibitors and tricyclic antidepressants. Since then, the
availability of a host of newer medications with better side effect
profiles has greatly increased our ability to safely treat a
significant percentage of patients. However, the newer medications
are largely drugs that merely augment or otherwise potentiate the
effects of the existing drugs by exerting their primary biochemical
effects by increasing the intrasynaptic levels of monoamines.
[0008] Unfortunately, current medications for the treatment of
depression take weeks to months to achieve their full effects and
in the meantime, patients continue to suffer from their symptoms
and continue to be at risk of self-harm as well as harm to their
personal and professional lives. Indeed, the lag period of onset of
action of several weeks of traditional antidepressants is
recognized as a major limitation, resulting in considerable
morbidity and high risk of suicidal behavior especially in the
first 9 days of starting antidepressants [3]. Pharmacological
strategies that have rapid onset of antidepressant effects within
hours or a few days and that are sustained would therefore have an
enormous impact on public health.
[0009] Recently, an "initiation and adaptation" paradigm for
understanding the delayed therapeutic actions of antidepressants
has been proposed [4]. This paradigm posits that the effect of
acute drug administration is mediated via an initial direct target
protein perturbation (e.g. binding to a monoamine transporter,
thereby resulting in monoamine reuptake inhibition); with repeated
administration, the same initial event, over time, leads to
enduring adaptive changes in critical neuronal networks, thereby
resulting in stable long-term antidepressant effects. Thus, this
paradigm posits that the delay in the therapeutic actions of
existing pharmacologic agents is due to the fact that they
initially act on proteins, which are considerably upstream of the
target genes, which are ultimately responsible for the
antidepressant effects. In this context, the major systems that
have been postulated to mediate the delayed adaptive effects of
antidepressants are neurotrophic signaling cascades and the
glutamatergic system [5].
[0010] The actions of antidepressants on neurotrophic signaling
cascades has been discussed by a number of groups [6-8]. The
context of the present application is with respect to the role of
the glutamatergic system, most notably the NMDA system, in the
actions of antidepressants [9-11], reviewed in [12]. NMDA receptor
antagonists have antidepressant effects in many animal models of
depression, including the application of inescapable stressors,
forced-swim, and tail suspension-induced immobility tests, in
learned helplessness models of depression, and in animals exposed
to a chronic mild stress procedure [13-18]. A single dose of the
NMDA antagonist ketamine in male Wistar rats interferes with the
induction of behavioral despair for up to 10 days after its
administration [19]. Additionally, repeated administration of
different classes of antidepressants--in a time frame consistent
with the delayed therapeutic effects--brings about alterations in
the expression of NMDA subunit mRNA [20] and radioligand binding to
these receptors in regions of the brain implicated in the
pathophysiology of depression [9].
[0011] Several lines of evidence also suggests that dysfunction of
the glutamatergic system may play an important role in the
pathophysiology of depression [reviewed in 21, 22]. Notably, a
recent study by Sanacora et al. showed glutamate levels in the
occipital cortex to be significantly elevated, in 29
medication-free subjects with unipolar major depression, as
compared to 28 age- and gender-matched healthy controls [23].
Together, these data support the hypothesis of regional alterations
in glutamatergic signaling in mood disorders. Finally, in clinical
trials, the glutamatergic modulators lamotrigine and riluzole (both
inhibitors of glutamate release) were found to have antidepressant
properties [24-26].
[0012] Ketamine has been used in the treatment of breakthrough pain
(BTP) in chronic pain patients. In such patients, 10-50 mg of
ketamine has been administered through intranasal administration in
incremental 10 mg doses, every 90 seconds. The effect of that
intranasal administration of ketamine was that there was a lower
BTP in patients that received intranasal ketamine as opposed to
placebo. There were very few side effects with such administration
[47].
[0013] Transdermal administration of ketamine has also been used
for the treatment of intractable neuropathic pain [87]. Results
indicated that subjects given a dose of 75 mg showed significant
improvement in pain disability, and subjective physical and mental
function. Azevedo et al. [88] report the results of a randomized,
double-blind, placebo-controlled trial using racemic ketamine in a
transdermal delivery system after minor abdominal gynecological
surgery using lidocaine epidural blockade. At the end of the
surgical procedure, a controlled delivery transdermal patch
containing either ketamine (25 mg/24 hours) or placebo was applied.
The time to rescue analgesic was longer in the ketamine group
(230.+-.112 minutes) compared to the placebo group (94.+-.54
minutes).
[0014] The limitations in sustaining disorder remission are
increasingly apparent for standard treatments of
treatment-resistant depression. The first phase of the STAR*D
study, the largest effectiveness study of its kind in "real world"
patients, measured the efficacy of a SSRI, citalopram, in
outpatients with depression (n=2,876). Remission rates were 28%, a
similar remission rate to that achieved in standard randomized
placebo-controlled acute efficacy trials [48]. As the presence of
residual symptoms is a strong predictor of relapse or recurrence
[49], therapeutic strategies going forward require a focus on
achieving and sustaining remission, by presumably addressing core
pathophysiological processes. Thus, it is evident that new methods
are needed for the treatment of chronic major depression that is
resistant to treatment.
SUMMARY OF THE INVENTION
[0015] Methods and compositions for the treatment of
treatment-resistant depression are described. More specifically,
the invention demonstrates that intranasal administration of
ketamine is effective to ameliorate the symptoms of
treatment-resistant depression. In particular embodiments, the
invention thus provides a method of treating a human patient for
treatment-resistant depression, comprising intranasally
administering a composition comprising ketamine to the patient at a
dosage sufficient to reduce or eliminate the symptoms of the
treatment-resistant depression. In more specific embodiments, the
ketamine is in a pharmaceutically acceptable carrier and is
administered at a dose of between about 0.1 mg/kg per day to about
3.0 mg/kg/day.
[0016] In specific embodiments, the symptoms of the
treatment-resistant depression are alleviated within 2 hours of
intranasal administration of the ketamine.
[0017] The methods of the invention may be achieved through a
method that comprises intranasal administration of a single dose of
the ketamine. Alternatively, multiple doses of ketamine may be
administered. In specific embodiments, a single intranasal
administration of the ketamine is sufficient to alleviate the
effects of the depression for 7 days, and in some cases,
longer.
[0018] In other aspects of the invention, the method may further
comprise administering a pharmaceutically effective dose of a
second agent, wherein the second agent is an antidepressant agent.
The additional agent may be any addition antidepressant agent.
Exemplary such antidepressant agents include but are not limited to
at least one member of lithium, a pharmaceutical antidepressant, an
herbal antidepressant, an anticonvulsant, a mood stabilizer, an
antipsychotic agent, and a benzodiazepine.
[0019] Also contemplated herein is a kit comprising a carrier for
delivering a ketamine intranasally containing in close confinement
therein one or more components, wherein: a) a first component
contains ketamine; and b) a second component contains a
psychotropic medication useful in the treatment of depression. In a
further aspect of the invention, the 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.
[0020] Also provided in the present invention is a device for
patient self-administration of ketamine comprising a nasal spray
inhaler containing an aerosol spray formulation of ketamine and a
pharmaceutically acceptable dispersant, wherein the device is
metered to disperse an amount of the aerosol formulation by forming
a spray that contains a dose of ketamine effective to alleviate
depression but which dose of ketamine is determined by a physician
or medical care provider to be below a level that causes dysphoria
or psychosis.
[0021] In alternative embodiments, intravenous and transdermal
administration of ketamine are contemplated. In one alternative
embodiment, the invention thus provides a method of treating a
human patient for treatment-resistant depression, comprising
intravenously administering a composition comprising ketamine to
the patient at a dosage sufficient to reduce or eliminate the
symptoms of the treatment-resistant depression. In another
alternative embodiment, the invention thus provides a method of
treating a human patient for treatment-resistant depression,
comprising transdermally administering a composition comprising
ketamine to the patient at a dosage sufficient to reduce or
eliminate the symptoms of the treatment-resistant depression. In
more specific embodiments, the ketamine is in a pharmaceutically
acceptable carrier and is administered at a dose of between about
0.1 mg/kg per day to about 3.0 mg/kg/day.
[0022] In specific embodiments, the symptoms of the
treatment-resistant depression are alleviated within 2 hours of
administration of the ketamine.
[0023] The methods of the invention may be achieved through a
method that comprises intravenous or transdermal administration of
multiple doses of the ketamine. In specific embodiments, the
ketamine is administered at least two, at least three, at least
four, at least five, at least six, at least seven, at least eight,
at least nine times in fourteen days. In other embodiments, the
ketamine is administered at least two, at least three, at least
four, at least five, at least six, at least seven, at least eight,
at least nine times in twenty-one days.
[0024] In other aspects of the invention, the method may further
comprise administering a pharmaceutically effective dose of a
second agent, wherein the second agent is an antidepressant agent.
The additional agent may be any addition antidepressant agent.
Exemplary such antidepressant agents include but are not limited to
at least one member of lithium, a pharmaceutical antidepressant, an
herbal antidepressant, an anticonvulsant, a mood stabilizer, an
antipsychotic agent, and a benzodiazepine.
[0025] Also provided in the present invention is a device for
patient self-administration of ketamine comprising a transdermal
patch containing a formulation of ketamine and a pharmaceutically
acceptable carrier, wherein the device is metered to disperse an
amount of the formulation that contains a dose of ketamine
effective to alleviate depression but which dose of ketamine is
determined by a physician or medical care provider to be below a
level that causes dysphoria.
[0026] Other features and advantages of the invention will become
apparent from the following detailed description. It should be
understood, however, that the detailed description and the specific
examples, while indicating preferred embodiments of the invention,
are given by way of illustration only, because various changes and
modifications within the spirit and scope of the invention will
become apparent to those skilled in the art from this detailed
description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The following drawings form part of the present
specification and are included to further illustrate aspects of the
present invention. The invention may be better understood by
reference to the drawings in combination with the detailed
description of the specific embodiments presented herein.
[0028] FIG. 1 Enrollment, randomization, withdrawals and completion
of the two treatment phases (n=18)
[0029] FIG. 2 Change in 21 HDRS, BPRS positive symptoms and YMRS
scores over one week (n=18). Abbreviations: BPRS Brief Psychiatric
Rating Scale; HDRS: Hamilton Depression Rating Scale; YMRS: Young
Mania Rating Scale.
[0030] FIG. 3A Portion of responders (50% improvement on HDRS) to
ketamine and placebo from minute 40 to day 7 post-infusion
(n=18).
[0031] FIG. 3B Portion of remitters (HDRS <7) to ketamine and
placebo from minute 40 to day 7 post-infusion (n=18).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE
INVENTION
[0032] Existing therapies for major depression have a lag of onset
of action of several weeks, resulting in considerable morbidity and
high risk of suicidal behavior. Exploring pharmacological
strategies that have rapid onset of antidepressant effects within a
few days and that are sustained would have an enormous impact on
patient care. Converging lines of evidence suggest the role of the
glutamatergic system in the pathophysiology and treatment of mood
disorders.
[0033] Based on the preclinical and preliminary clinical studies,
the inventors postulated that the NMDA receptor complex may mediate
the delayed therapeutic effects of traditional monoaminergic based
antidepressants, and furthermore that directly targeting the NMDA
receptor would bring about rapid antidepressant effects. Indeed, in
a preliminary study of 7 subjects with major depression, it was
reported that a single intravenous dose of the high-affinity NMDA
receptor antagonist ketamine resulted in a rapid and short-lived
antidepressant effect [27]. In the present invention, the inventors
have performed studies to determine if ketamine does indeed exert
rapid antidepressant effects in a relatively refractory population,
and furthermore, if these effects of a single dose of ketamine are
sustained.
[0034] The exemplary data provided herein were obtained from a
randomized, placebo-controlled, double-blind crossover study on
patients that had DSM-TV (Diagnostic and Statistical Manual of
Mental Disorders, fourth edition; DSM-IV) treatment-resistant major
depression. The term "treatment-resistant major depression" refers
to the depression experienced by any subject who has not previously
responded to two adequate antidepressant trials (adequacy of
antidepressant trials were determined with the Antidepressant
Treatment History Form). Treatment-resistant major depression is a
relatively common occurrence in clinical practice, with up to 50 to
60% of patients not achieving adequate response following
antidepressant treatment [52]. At a minimum, treatment
resistant-depression includes unipolar depression that does not
respond satisfactorily to one or more treatments that are optimally
delivered [53]. If the depression has not benefited from at least
two adequate trials of medications from different classes in the
current episode, clinically significant resistance is present [54].
Several schemes to "stage" the degree of resistance have been
proposed. The most widely accepted scheme uses the staging system
of Thase and Rush [55]. The stages of resistance are as
follows:
[0035] Stage I: Failure of at least one adequate trial of one major
class of antidepressant;
[0036] Stage II: Stage I resistance plus failure of adequate trial
of an antidepressant in a distinctly different class from that used
in Stage I
[0037] Stage III: Stage II resistance plus failure of an adequate
trial of a TCA
[0038] Stage IV: Stage III resistance plus failure of an adequate
trial of a MAOI
[0039] Stage V: Stage IV resistance plus failure of a course of
bilateral ECT
[0040] Thus, from the above schemes, the skilled person may
understand treatment-resistant depression patients to include
patients that have failed to respond to one adequate trial of an
antidepressant (Stage I).
[0041] Another staging system takes into consideration both the
number of failed trials as well as the intensity/optimization of
each trial, and does not make assumptions regarding a hierarchy of
antidepressant classes. Massachusetts General Hospital (MGH)
Staging Method to Classify Treatment-Resistant Depression:
[0042] (1) Non-response to each adequate (at least 6 weeks of an
adequate dose of antidepressant) trial of a marketed antidepressant
generates an overall score of resistance (1 point per trial);
[0043] (2) Optimization of dose, optimization of duration, and
augmentation/combination of each trial (based on the MGH or
Antidepressant Treatment Response Questionnaire) increase the
overall score (0.5 point per trial per optimization/strategy);
[0044] (3) ECT increases the overall score by 3 points ECT,
electroconvulsive therapy.
[0045] Finally, many researchers use the guidelines proposed by the
Antidepressant Treatment History Form (ATHF, Sackeim 2001,
Neuropsychopharmacology 25: 713-728). The Antidepressant Treatment
History Form defines the adequacy of the treatment on a continuum
for both dose and duration, providing categories rated 0 through 4.
The ATHF provides for different levels of resistance. A level 3
degree of resistance for fluoxetine, for example, requires at least
4 weeks of fluoxetine at at least 20 mg/day. Although they are
somewhat arbitrary, these benchmarks do reflect reasonable clinical
distinctions among previous treatment trials. Validation of this
approach has been achieved for acute phase treatment response to
electroconvulsive therapy (ECT) and vagus nerve stimulation
(VNS).
[0046] Thus, the patient population to be treated by the present
invention may be defined according to any one or more of the above
schemes. After a 2-week drug-free period, exemplary subjects having
treatment-resistant depression were given an intravenous infusion
of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test
days, a week apart. Subjects were rated at baseline and at 40, 80
minutes, 110 minutes, 230 minutes and days 1, 2, 3 and 7
post-infusion. The outcome of the treatment was measured using
changes in scores on the primary efficacy to measure the 21-item
Hamilton Depression Rating Scale (HDRS). From these studies it was
shown that subjects on ketamine showed significant improvement in
depression compared to placebo within 110 minutes after injection
that remained significant throughout the following week. The effect
size for the drug difference was very large (d=1.46, 95% C.I.
0.91-2.01) after 24 hours and moderate to large (d=0.68, 95% C.I.
0.13-1.23)) after 1 week. Of the subjects treated with ketamine,
71% met response and 29% met remission criteria the day following
ketamine infusion. Thirty-five percent of subjects maintained
response for at least 1 week. From these data it can be concluded
that robust and rapid antidepressant effects can result from a
single intravenous dose of an NMDA antagonist; onset of improvement
was evident within 2 hours post-infusion and continued to remain
significant for 1 week.
[0047] The present invention is directed to methods and
compositions for treating treatment-resistant depression using
intranasal administration of ketamine. Such a treatment may be
administered alone or may be supplemented with other antidepressant
therapies as described below.
[0048] Intravenous administration of ketamine also has been used
for the treatment of treatment-resistant major depression. In that
study, a 0.5 mg/kg intravenous infusion was given over 40 minutes.
Improvements in depression were seen within 2 hours post-injection;
and continued for up to 1 week. There were no serious adverse
events; ceased within 80 min post-infusion (euphoria, elevated BP,
increased libido, perceptual disturbances; Zarate et al, 2006).
[0049] Intranasal (IN) ketamine plasma levels used for pain is 3-4
fold lower than the intravenous (IV) ketamine studies in depression
[27, 78-86]. The slow infusion of ketamine produces gradually
increasing plasma levels during the infusion period. Dose-wise, the
typical ketamine dose for surgical induction is between 1.0-2.0
mg/kg, with additional ketamine used to sustain anesthesia. In
anesthesia, the target ketamine blood level is reached with
ketamine bolus doses between 0.2-0.26 mg/kg over 1 min, so the dose
for anesthesia is around 5 times less than the IV dose. The dose
for ketamine plasma levels to produce antidepressant responses as
opposed to the levels needed to produce anesthesia is in the range
of 0.5 mg/kg over 40 min. The reports of dissociation in the Carr
study and other pain studies were significantly lower than the IV
studies in MDD because the ketamine levels achieved intranasally in
these studies were much lower. The intranasal dose used for pain
(50 mg) is roughly equivalent to 0.1 mg/kg i.v. of ketamine.
[0050] In the present invention, the methods described are for the
treatment of depression in which up to 50 mg of ketamine is
administered intranasally. Such an administration may be
administered over a 1 hour time period or more or less. As
depression is a chronic illness requiring maintenance treatment, it
is expected that chronic administration of the intranasal
formulation may be employed as necessary, ranging from daily to
weekly, depending on response. Should the 50 mg IN dosage prove to
be inadequate to treat depression effectively increasing doses,
e.g., approximately 100 mg, approximately 150 mg, approximately 200
mg, approximately 250 mg total ketamine will be administered
intranasally, to establish the relative equivalent of the 0.5 mg/kg
dosage usage in the IV studies.
[0051] The intranasal administration of ketamine will be well
tolerated at the dosage used. In terms of efficacy, it is
contemplated that the positive results seen with treatment of
depression using an IV route of administration will be observed
with the intranasal.
[0052] In some embodiments, the intranasal ketamine formulation
will be used for an outpatient group of depressed patients who are
considered treatment-resistant. The intranasal formulation will
eliminate the necessity of patient presentation to a hospital or
clinic for intravenous administration. The patient can take
intranasal ketamine in their own home, with no need for a needle
stick. Thus, the acceptability of the treatment for patients will
be better than with the IV ketamine. The patient may be one that is
at least a moderately treatment-resistant patient, who is seeking
new options for the rapid and safe reduction of depressive
symptoms. The physician would monitor the patient as an outpatient,
and could adjust dosage as they would for an orally administered
medication.
[0053] Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone)
is a general anesthetic used by anesthesiologists, veterinarians,
and researchers. Nasal administration of ketamine and midazolam to
achieve sedation for ophthalmic surgery, and to induce anesthesia
prior to elective surgery in healthy children has been reported
[50, 51]. Usually, ketamine is administered intramuscularly (i.m.)
or intravenously (i.v.) to induce anesthesia. However, intranasal
compositions of ketamine are available from e.g., Javelin
Pharmaceuticals.
[0054] Ketamine has also been known to have analgesic properties
[56]; analgesia can be achieved with subanesthetic doses of
ketamine [57, 58]. The drug is administered by various routes,
including i.v., i.m., caudal, intrathecal, and subcutaneous (s.c.).
Subcutaneous administration of ketamine has been used to treat pain
following surgery and associated with terminal cancer [see, e.g.,
59]. Ketamine hydrochloride administered via a subcutaneous cannula
was reported to successfully treat phantom limb pain [60].
[0055] As explained above, management of treatment-resistant
depression is complex and frequently unsuccessful. In the present
invention, it is shown that non-competitive N-methyl-D-aspartate
(NMDA) receptor antagonists, such as ketamine, will form a first
line defense against treatment-resistant depression if administered
through the nasal route.
[0056] The present invention is broadly directed to a method for
treating treatment-resistant depression. More particularly, the
inventors have discovered that administration via a nasal route of
a dose of ketamine is effective to alleviate depression in patients
suffering from treatment resistant depression. In a further
embodiment, the present invention provides for pulmonary
administration of ketamine by inhalation. Nasal administration of
an anti-depressant dose of ketamine advantageously allows for
patient self administration of the drug, which provides for
depression management on an outpatient basis. Moreover, ketamine
administration in nasal sprays and inhalers are generally socially
acceptable.
[0057] Another advantage of the invention is that it allows the
administration of lesser amount of a second anti-depressant agent
for the treatment of treatment-resistant depression. As such, in
some embodiments, the intranasal administration of the ketamine may
have an additive effect when administered in combination with
another antidepressant.
[0058] Ketamine is an inexpensive, readily available drug, with
minor adverse side effects. Thus, the invention contemplates
additional savings to the overburdened health care system. Nasal
administration of this agent is rapid, allowing for fast action of
the drug, and easily accomplished by a non-medically trained
patient.
[0059] In one aspect, the depression-alleviating dose of ketamine
is approximately 0.01 to approximately 1 mg/kg of body weight. In a
more preferred aspect, the dose of ketamine is approximately 0.05
to approximately 0.7 mg/kg of body weight. In another embodiment,
the total dose of ketamine per nasal administration ranges from
about 1 to about 250 mg.
[0060] In a specific aspect of the invention, the dose of ketamine
is effective to alleviate depression in a patient suffering from
treatment-resistant depression. In a particular aspect, nasal
administration of ketamine can be a supplemental therapy in a
depression management regimen that include administration of one or
more additional antidepressant agents. Such additional agents may
be administered through a nasal route or through another route. The
additional agents may be administered concurrently with the
ketamine or before or after the ketamine administration.
[0061] The ketamine may be provided in a metered dose which is well
below the level associated with dysphoria or hallucination. In
other aspects the dose of the second antidepressant agent is
provided in an amount effective to alleviate depression with the
ketamine; preferably the second antidepressant agent is
administered via the mucosal route with the ketamine.
[0062] The invention provides a device for patient
self-administration of ketamine, which device comprises a nasal
inhaler containing an aerosol formulation of ketamine and a
pharmaceutically acceptable dispersant, wherein the device is
metered to disperse an amount of the aerosol formulation that
contains a dose of ketamine effective to alleviate depression. The
dispersant may be a surfactant, such as, but not limited to,
polyoxyethylene fatty acid esters, polyoxyethylene fatty acid
alcohols, and polyeoxyethylene sorbitan fatty acid esters.
Phospholipid-based surfactants also may be used.
[0063] In other embodiments, the aerosol formulation of ketamine is
provided as a dry powder aerosol formulation in which the ketamine
is present as a finely divided powder. The dry powder formulation
can further comprise a bulking agent, such as, but not limited to,
lactose, sorbitol, sucrose and mannitol.
[0064] In another specific embodiment, the aerosol formulation is a
liquid aerosol formulation further comprising a pharmaceutically
acceptable diluent, such as, but not limited to, sterile water,
saline, buffered saline and dextrose solution.
[0065] In further embodiments, the aerosol formulation further
comprises a second antidepressant agent in a concentration such
that the metered amount of the aerosol formulation dispersed by the
device contains a dose of the second agent in a metered amount that
is effective to ameliorate the symptoms of depression when used in
combination with the ketamine.
[0066] Thus, the invention provides a self administration method
for outpatient treatment of treatment-resistant depression. Such
administration may be used in a hospital, in a medical office or
outside a hospital or medical office by non-medical personnel for
nasal self administration of ketamine.
[0067] The present invention is based on the surprising and
unexpected discovery that nasal administration of ketamine can
alleviate symptoms of chronic, treatment-resistant depression.
Thus, patients that have previously been refractory to treatment
with antidepressants, was able to achieve more satisfactory
depression management by nasal administration of 8-32 mg of
ketamine, corresponding to [0.13 to 0.53] mg/kg of body weight.
However, it is contemplated that up to 250 mg of ketamine may be
administered intranasally for the treatment of depression. In one
preferred embodiment, a ketamine dosage of 0.5 mg/kg was effective
to improve mood at 40 minutes through 7 days in patients that
previously manifested treatment-resistant depression. The invention
shows a robust and rapid (within hours of intranasal
administration) and relatively sustained (effects lasting 1 week)
response to even a single-dose of the NDMA antagonist ketamine.
Notably, subjects treated with intranasal ketamine were better than
placebo within 2 hours (110 minutes) and remained better through 7
days. In addition, the invention also shows that IV administration
of f ketamine can alleviate symptoms of chronic,
treatment-resistant depression. Thus, patients that have previously
been refractory to treatment with antidepressants, was able to
achieve more satisfactory depression management by IV
administration of ketamine. Again, subjects treated with IV
ketamine were better than placebo within 2 hours (110 minutes) and
remained better through 7 days.
[0068] Any chronic, treatment-resistant depression may be treated
by the methods described herein. Such depression may include but is
not limited to any of: major depressive disorder, single episode,
recurrent major depressive disorder-unipolar depression, seasonal
affective disorder-winter depression, bipolar mood disorder-bipolar
depression, mood disorder due to a general medical condition-with
major depressive-like episode, or mood disorder due to a general
medical condition-with depressive features, wherein those disorders
are resistant to treatment in a given patient. Thus, any patient
that presents one of those disorders and who has not responded to
an adequate trial of one antidepressant in the current episode and
has recurrent or chronic depressive symptoms for greater than 2
years can be treated by the methods of the invention. Manic
Depressive illnesses are also described in Goodwin, et al.,
[61].
[0069] There are three types of depression generally characterized
in the art, major depression, dysthymic disorder, or dysthymia, and
depressive disorder not otherwise specified. Major depression is
characterized by peak episodes of extreme depression. During a peak
episode, the patient may suffer from depressed mood, and markedly
diminished interest or pleasure in activities. Other symptoms
include significant weight loss or weight gain, decrease or
increase in appetite, insomnia or hypersomnia, psychomotor
agitation or retardation, fatigue or loss of energy, feelings of
worthlessness or excessive or inappropriate guilt, diminished
ability to think or concentrate or indecisiveness, recurrent
thoughts of death, suicidal ideation or suicidal attempts. Symptoms
last for at least two weeks and cause significant distressor
impairment in important areas of functioning.
[0070] Dysthymia is characterized by depressed mood for at least 2
years as well as other symptoms like poor appetite or overeating,
insomnia or hypersomnia, low energy or fatigue, low self esteem,
poor concentration or difficulty making decisions and feelings of
hopelessness. As is recognized in the field of psychiatric arts,
depression may also comprise, and/or may also manifest itself in a
variety of forms, including but not limited to, seasonal affective
disorder, diurnal mood variations, or depression associated with
menopause. Diagnostic criteria for dysthymia and major depression,
as well as for seasonal affective disorder, diurnal mood variations
and depression associated with menopause, are more fully explained
in the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, (DSM IV) published by the American Psychiatric
Association or by the ICD (ICD-10: International Statistical
Classification of Diseases and Related Health Problems (10th
Revision) or any other psychiatric classification system.
[0071] Depression with seasonal affective pattern or seasonal
affective disorder (hereinafter referred to as "SAD") is also known
as cabin fever, evening blues, and sun deprivation syndrome. The
terms "seasonal affective disorder" or "seasonal pattern specifier"
are defined in the DSM-IV as a specifier or adjective that more
precisely characterize feature associated with depression. A
particular feature of SAD is the regular occurrence of depression
in winter.
[0072] Most of the patients with SAD are characterized by an
atypical type of depression in the winter which is associated with
mood reactivity (mood brightens in response to actual or potential
positive events) as well as weight gain or increase in appetite,
hypersomnia, leaden paralysis (heavy, leaden feelings in arms or
legs), long-standing pattern of interpersonal rejection
sensitivity.
[0073] The diagnosis of depression usually follows a clinical
evaluation by a psychiatrist or other mental health professionals.
The two most recognized sets of diagnostic criteria for major
depressive disorder and other depressive, or mood disorders, are
outlined in the DSM, Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, (DSM IV) published by the American
Psychiatric Association and the ICD (ICD-10: International
Statistical Classification of Diseases and Related Health
Problems-10th Revision, published periodically by the World Health
Organization) or any other psychiatric classification system.
[0074] The presence and the severity of the depressive state can
also be determined with structured and semi-structured interview
and questioners such as the Hamilton score that is well known in
the art. [62]. Accordingly, the present invention is directed of
methods for alleviating treatment-resistant depression on an
outpatient basis by nasal administration of ketamine, and to
devices usable by non-medical personnel for nasal
self-administration of ketamine.
[0075] Ketamine will preferably be prepared in a formulation or
pharmaceutical composition appropriate for nasal administration.
Suitable formulations are discussed in detail, infra. In a further
embodiment, ketamine can be formulated with a mucosal penetration
enhancer to facilitate delivery of the drug. The formulation can
also be prepared with pH optimized for solubility, drug stability,
absorption through nasal mucosa, and other considerations.
[0076] The invention provides for administration of a
therapeutically effective dose of ketamine, i.e., a dose effective
to alleviate treatment-resistant depression. The actual dose will
vary, depending on the body weight of the patient, the severity of
the depression, the route of administration, the nature of
medications administered concurrently, the number of doses to be
administered per day, and other factors generally considered by the
ordinary skilled physician in the administration of drugs. In a
specific embodiment, the amount of ketamine administered to a
patient suffering from treatment-resistant depression is about 10%
to about 20% of the amount used to induce anesthesia. In another
specific embodiment, the dose of ketamine is about 0.01 mg per kg
of body weight (0.01 mg/kg) to about 1 mg/kg; preferably about 0.05
mg/kg to about 0.7 mg/kg. In yet another embodiment, the dose
ranges from about 1 mg to about 250 mg. A dose of any integer
between these two numbers is contemplated. Thus, for example,
intranasal, transdermal, intravenous, intradermal, or subcutaneous
formulations respectively containing total intranasal, transdermal,
intravenous, intradermal, or subcutaneous doses of 1 mg, 2 mg, 4
mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg,
50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95
mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg,
180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg are
specifically contemplated. Preferably, the effective dose is
titrated under the supervision of a physician or medical care
provider, so that the optimum dose for the particular application
is accurately determined. Thus, the present invention provides a
dose suited to each individual patient.
[0077] Once the dosage range is established, a further advantage of
the invention is that the patient can administer ketamine on an
as-needed, dose-to-effect basis. Thus, the frequency of
administration is under control of the patient. However, the
relatively low dose with each administration will reduce the
possibilities for abuse.
[0078] Yet another particular advantage of the present invention is
that nasal administration of ketamine is non-invasive, and provides
for introduction into the bloodstream almost as fast as i.v.
administration, and much faster than perioral administration.
[0079] More importantly, a patient can control administration of
the antidepressant medication, because nasal administration
provides for precise control over the dosage and effect of the drug
used to offset changes in depression throughout an administration
period. Nasal administration of ketamine optimally provides for
dose-to-effect administration of the drug.
[0080] The term "nasal administration" in all its grammatical forms
refers to administration of a drug through the nasal mucous
membrane to the bloodstream for systemic delivery of the drug. The
advantages of nasal administration for drug delivery are that it
does not require injection using a syringe and needle, it avoids
necrosis that can accompany i.m. administration of drugs, and
trans-mucosal administration of a drug is highly amenable to self
administration.
[0081] The present invention contemplates pulmonary administration
through an inhaler.
[0082] The ketamine may be formulated with a "mucosal penetration
enhancer," i.e., a reagent that increases the rate or facility of
transmucosal penetration of ketamine, such as but not limited to, a
bile salt, fatty acid, surfactant or alcohol. In specific
embodiments, the permeation enhancer can be sodium cholate, sodium
dodecyl sulphate, sodium deoxycholate, taurodeoxycholate, sodium
glycocholate, dimethylsulfoxide or ethanol.
[0083] A "therapeutically effective amount" of a drug is an amount
effective to demonstrate a desired activity of the drug. According
to the instant invention, a therapeutically effective amount of
ketamine is an amount effective to alleviate, i.e., noticeably
reduce, the symptoms of treatment-resistant depression patient.
[0084] Those skilled in the art are well aware of nasal
administration of ketamine for treating pain (see U.S. Pat. No.
5,543,4354, incorporated herein by reference in its entirety)
Through such nasal and pulmonary administration of ketamine and
additional therapeutically active drugs or agents with which
ketamine can be administered to treat depression as discussed
herein.
[0085] The present invention contemplates formulations comprising
ketamine for use in a wide variety of devices that are designed for
the delivery of pharmaceutical compositions and therapeutic
formulations to the respiratory tract, preferably the nasal
passages. The preferred route of administration of the present
invention is in an aerosol spray for nasal inhalation. Ketamine,
combined with a dispersing agent, or dispersant, can be
administered in an aerosol formulation as a dry powder or in a
solution or suspension with a diluent.
[0086] As used herein, the term "aerosol" refers to suspension in
the air. In particular, aerosol refers to the particlization or
atomization of a formulation of the invention and its suspension in
the air. According to the present invention, an aerosol formulation
is a formulation comprising ketamine for nasal inhalation or
pulmonary administration.
[0087] As used herein, the term "inhaler" refers both to devices
for nasal and pulmonary administration of a drug, e.g., in
solution, powder and the like. For example, a the term "inhaler" is
intended to encompass a propellant driven inhaler, such as is used
for to administer antihistamine for acute asthma attacks, and
plastic spray bottles, such as are used to administer
decongestants.
[0088] As used herein, the term "dispersant" refers to an agent
that assists aerosolization of the ketamine or absorption of the
ketamine in mucosal tissue, or both. In a specific aspect, the
dispersant can be a mucosal penetration enhancer. Preferably, the
dispersant is pharmaceutically acceptable. As used herein, the term
"pharmaceutically acceptable" means approved by a regulatory agency
of the Federal or a state government or listed in the U.S.
Pharmacopeia or other generally recognized pharmacopeia for use in
animals, and more particularly in humans.
[0089] Suitable dispersing agents are well known in the art, and
include but are not limited to surfactants and the like. Such
surfactants are generally used in the art to reduce surface induce
aggregation of ketamine caused by atomization of the solution
forming the liquid aerosol and may be used in the methods and
devices of the present invention. Examples of such surfactants
include, but are not limited to, surfactants such as
polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene
sorbitan fatty acid esters. Amounts of surfactants used will vary,
being generally within the range or 0.001 and 4% by weight of the
formulation. Suitable surfactants are well known in the art, and
can be selected on the basis of desired properties, depending on
the specific formulation, concentration of ketamine, diluent (in a
liquid formulation) or form of powder (in a dry powder
formulation), etc.
[0090] The liquid aerosol formulations contain ketamine and a
dispersing agent in a physiologically acceptable diluent. The dry
powder aerosol formulations of the present invention consist of a
finely divided solid form of ketamine and a dispersing agent. With
either the liquid or dry powder aerosol formulation, the
formulation must be aerosolized. That is, it must be broken down
into liquid or solid particles in order to ensure that the
aerosolized dose actually reaches the mucous membranes of the nasal
passages or the lung. The term "aerosol particle" is used herein to
describe the liquid or solid particle suitable for nasal or
pulmonary administration, i.e., that will reach the mucous
membranes. Other considerations, such as construction of the
delivery device, additional components in the formulation, and
particle characteristics are important. These aspects of nasal or
pulmonary administration of a drug are well known in the art, and
manipulation of formulations, aerosolization means and construction
of a delivery device require at most routine experimentation by one
of ordinary skill in the art.
[0091] In a particular embodiment, the mass median dynamic diameter
will be 5 micrometers or less in order to ensure that the drug
particles reach the lung alveoli (Wearley, L. L., 1991, 1991, Crit.
Rev. in Ther. Drug Carrier Systems 8:333).
[0092] With regard to construction of the delivery device, any form
of aerosolization known in the art, including but not limited to
spray bottles, nebulization, atomization or pump aerosolization of
a liquid formulation, and aerosolization of a dry powder
formulation, can be used in the practice of the invention.
[0093] As noted above, in a preferred aspect of the invention, the
device for aerosolization is a metered dose inhaler. A metered dose
inhaler provides a specific dosage when administered, rather than a
variable dose depending on administration. Such a metered dose
inhaler can be used with either a liquid or a dry powder aerosol
formulation. Metered dose inhalers are well known in the art.
[0094] For nasal administration, a useful device is a small, hard
bottle to which a metered dose sprayer is attached. In one
embodiment, the metered dose is delivered by drawing the ketamine
solution into a chamber of defined volume, which chamber has an
aperture dimensioned to aerosolize and aerosol formulation by
forming a spray when a liquid in the chamber is compressed. The
chamber is compressed to administer the ketamine. In a specific
embodiment, the chamber is a piston arrangement. Such devices are
commercially available.
[0095] Alternatively, a plastic squeeze bottle with an aperture or
opening dimensioned to aerosolize an aerosol formulation by forming
a spray when squeezed. The opening is usually found in the top of
the bottle, and the top is generally tapered to partially fit in
the nasal passages for efficient administration of the aerosol
formulation. Preferably, the nasal inhaler will provide a metered
amount of the aerosol formulation, for administration of a measured
dose of the drug.
[0096] Often, the aerosolization of a liquid or a dry powder
formulation for inhalation into the lung will require a propellent.
The propellent may be any propellant generally used in the art.
Specific nonlimiting examples of such useful propellants are a
chloroflourocarbon, a hydrofluorocarbon, a hydochlorofluorocarbon,
or a hydrocarbon, including trifluoromethane,
dichlorodiflouromethane, dichlorotetrafluoroethanol, and
1,1,1,2-tetraflouroethane, or combinations thereof.
[0097] Systems of aerosol delivery, such as the pressurized metered
dose inhaler and the dry powder inhaler are disclosed in Newman, S.
P., Aerosols and the Lung, Clarke, S. W. and Davia, D. editors, pp.
197-22 and can be used in connection with the present
invention.
[0098] In general, the ketamine is introduced into the subject in
the aerosol form in an amount between about 0.01 mg per kg body
weight of the mammal up to about 1 mg per kg body weight of said
mammal. In a specific embodiment, the dosage is administered as
needed. One of ordinary skill in the art can readily determine a
volume or weight of aerosol corresponding to this dosage based on
the concentration of ketamine in an aerosol formulation of the
invention.
[0099] The present invention provides liquid aerosol formulations
and dosage forms for use in treating subjects suffering from
treatment-resistant depression. In general such dosage forms
contain ketamine in a pharmaceutically acceptable diluent.
Pharmaceutically acceptable diluents in such liquid aerosol
formulations include but are not limited to sterile water, saline,
buffered saline, dextrose solution, and the like. In a specific
embodiment, a diluent that may be used in the present invention or
the pharmaceutical formulation of the present invention is
phosphate buffered saline or a buffered saline solution generally
between the pH 7.0-8.0 range, or water.
[0100] The liquid aerosol formulation also may optionally include
pharmaceutically acceptable carriers, diluents, solubilizing or
emulsifying agents, surfactants and excipients.
[0101] The formulation may include a carrier. The carrier is a
macromolecule which is soluble in the circulatory system and which
is physiologically acceptable where physiological acceptance means
that those of skill in the art would accept injection of said
carrier into a patient as part of a therapeutic regime. The carrier
preferably is relatively stable in the circulatory system with an
acceptable plasma half life for clearance. Such macromolecules
include but are not limited to Soya lecithin, oleic acid and
sorbitan trioleate, with sorbitan trioleate preferred.
[0102] The formulations of the present embodiment may also include
other agents useful for pH maintenance, solution stabilization, or
for the regulation of osmotic pressure. Examples of the agents
include but are not limited to salts, such as sodium chloride, or
potassium chloride, and carbohydrates, such as glucose, galactose
or mannose, and the like.
[0103] The present invention further contemplates liquid aerosol
formulations comprising ketamine and another therapeutically
effective drug, such as a described in further detail below.
[0104] It is also contemplated that the present aerosol formulation
can be prepared as a dry powder formulation comprising a finely
divided powder form of ketamine and a dispersant. For example, the
dry powder formulation can comprise a finely divided dry powder
containing ketamine, a dispersing agent and also a bulking agent.
Bulking agents useful in conjunction with the present formulation
include such agents as lactose, sorbitol, sucrose, or mannitol, in
amounts that facilitate the dispersal of the powder from the
device.
[0105] In a further embodiment, an aerosol formulation of the
present invention can include other therapeutically or
pharmacologically active ingredients in addition to ketamine, such
as but not limited to a conventional antidepressant therapies that
include, but are not limited to: antidepressants: biogenic amine
non-selective reuptake inhibitors, e.g., tricyclic antidepressants
like Imipramine; serotonin selective reuptake inhibitors like
Fluoxetine (Prozac); monoamine oxidase inhibitors (MAO-I) like
phenelezine; other types of antidepressant medications including
atypical antidepressants. Antidepressants augmentation with other
medications e.g., lithium, T3, T4, etc. Other treatment modalities
with antidepressant effects: electro-convulsive treatment (ECT);
light therapy psychotherapy e.g., cognitive or interpersonal
therapy for depression.
[0106] In addition, administration of drugs, reported to ameliorate
or exacerbate the symptoms of a neuropsychiatric disorder, include
but are not limited to compounds include antidepressants such as
lithium salts, carbamazepine, valproic acid, lysergic acid
diethylamide (LSD), p-chlorophenylalanine, p-propyidopacetamide
dithiocarbamate derivatives e.g., FLA 63; anti-anxiety drugs, e.g.,
diazepam; monoamine oxidase (MAO) inhibitors, e.g., iproniazid,
clorgyline, phenelzine, tranylcypromine, and isocarboxazid;
biogenic amine uptake blockers, e.g., tricyclic antidepressants
such as desipramine, imipramine and amitriptyline; atypical
antidepressants such as mirtazapine, nefazodone, bupropion;
serotonin reuptake inhibitors e.g., fluoxetine, venlafaxine, and
duloxetine; antipsychotic drugs such as phenothiazine derivatives
(e.g., chlorpromazine (thorazine) and trifluopromazine)),
butyrophenones (e.g., haloperidol (Haldol)), thioxanthene
derivatives (e.g., chlorprothixene), S and dibenzodiazepines (e.g.,
clozapine); benzodiazepines; dopaminergic agonists and antagonists
e.g., L-DOPA, cocaine, amphetamine, a-methyl-tyrosine, reserpine,
tetrabenazine, benztropine, pargyline; noradrenergic agonists and
antagonists e.g., clonidine, phenoxybenzamine, phentolamine,
tropolone. In another embodiment of the treatment methods, the
compounds administered comprise compounds, in particular drugs,
reported to ameliorate or exacerbate the symptoms of oxidative
stress disorder. Such compounds include reduced IS glutathione
(GSH), glutathione precursors, e.g., N-acetylcysteine;
antioxidants, e.g., vitamins E and C, beta carotene and quinones;
inhibitors of lipid membrane peroxidation, e.g., 21-aminosteroid
U74006F (tirilazad mesylate), and lazaroids; antioxidants such as
mazindol; 2c dizocilpine maleate; selegiline; sulfhydryls
N-acetyleysteine and cysteamine; dimethylthiourea; EUK-8 a
synthetic, low molecular salen-manganese complex; synthetic
manganese-based metalloprotein superoxide dismutase mimic, SC52608;
free radical scavengers or suppressors, e.g., pegorgotein,
tocotrienol, tocopheral, MDL 74,18, LY231617, MCI-186, AVS
(nicaraven), allopurinol, rifampicin, oxypurinol, hypochlorous acid
or recombinant human Cu, Zn-SOD.
[0107] Co-administration of ketamine with a second therapeutic
agent such as those discussed above is provided in an amount
effective to alleviate one or more symptoms of treatment-resistant
depression.
[0108] The mild adverse effects of ketamine, e.g., dysphoria and/or
hallucinations, sometimes called "ketamine dreams," can occur upon
administration of a dose of greater than 50 mg of ketamine, and
usually require doses greater than 100 mg of ketamine of total dose
intranasally. One advantage of the present invention is that nasal
delivery of ketamine allows for control of the dose to a level
effective for analgesia, but below the level that results in such
dreams. However, it is possible that an individual may overdose,
particularly in response to an acute episode of depression. Thus,
co-administration of a ketamine with the additional exemplary
antidepressant agents noted above may be indicated in order to
achieve the beneficial anti-depressant effects of ketamine without
the side effects of this agent.
[0109] In a preferred embodiment, a therapeutically effective
amount of the second agent used for the treatment of depression
herein is administered in conjunction with ketamine. A
therapeutically effective amount of the second agent is an amount
effective to alleviate treatment-resistant depression when
co-administered with the ketamine.
[0110] As shown in the Examples below, patients treated with the
intranasal ketamine show remarkable recovery from depression. Such
patients may thus end up using decreased amounts of the other
antidepressant medications.
[0111] As discussed above, the present invention is directed to
various methods and compositions for treating treatment-resistant
depression comprising intranasal administration of ketamine. In an
alternative embodiment, the present invention contemplates
intravenous administration of ketamine for the treatment of
treatment-resistant depression. Such treatment may be administered
alone or may be supplemented with other antidepressant therapies as
described herein.
[0112] IV administration of ketamine (0.5 mg/kg over 40 minutes)
reported improvements in depression within 2 hours post-injection;
and continued for up to 1 week. There were no serious adverse
events caused by IV administration. Any side effects observed were
mild, e.g., euphoria, elevated BP, increased libido, perceptual
disturbances, and furthermore these effects abated within 80 min
post-infusion. A chronic infusion dosing strategy has been
previously described in two patients with depression (Correll et
al., Pain Medicine, 7: 92-95. 2006), beginning with IV infusion at
0.1-0.2 mg/kg/hour (15-20 mg/hour). In these cases, dosing was
maintained for 5 days, and the endpoint of titration was
psychotomimetic side effects. However, there is no report in the
literature of a tolerability threshold dose that is maintained for
an additional six to nine treatments.
[0113] The invention for the first time provides a method of
treating treatment-resistant depression comprising intravenous
administration of ketamine, wherein the administration is repeated
multiple times within a specific time period. For example, the
administration is administered at least twice, at least three
times, at least four times, at least five time, at least six times,
at least seven times, at least eight times, at least nine times, or
at least ten times over a period of two to three weeks.
[0114] In another alternative embodiment, the administration
comprises transdermal administration. Such treatment may be
administered alone or may be supplemented with other antidepressant
therapies as described herein. Transdermal administration includes
passive or active transdermal or transcutaneous modalities,
including, for example, patches and iontophoresis devices, as well
as topical application of pastes, salves, or ointments.
[0115] To date, there are only two published studies of transdermal
ketamine, both for use in pain disorder (Vranken et al.,
Pain.,118:224-31, 2005, Azevedo et al., Anesth Anal., 91: 1479-82,
2000). Neither of these studies provides any teaching of the
treatment of depression that is resistant to treatment. Vranken et
al. studied the use of an iontophoretic patch (a mechanism of
delivery in which the electrically charged drug is transmitted by
pulses of galvanic current) in 33 men and women with intractable
central neuropathic pain. Vranken et al. chose to use an enantiomer
of ketamine, S(+)-ketamine, a compound two times more potent than
racemic (which is a mixture of the S(+) and R (+)) (Schuettler et
al., Ketamine and its isomers, Textbook of Intravenous Anesthesia.
Edited by White PF. Baltimore, Williams & Wilkins, 1997, pp
171-88). Using a randomized, double-blind, placebo-controlled
design, subjects were administered either a dose of 50 mg (n=11),
75 mg (n=11), or placebo (n=11), delivered transdermally over 24
hours for 7 days. Vranken et al. found that although there was no
change among groups in pain intensity (measure by the Visual Analog
Scale), subjects given dose of 75 mg showed significant improvement
in pain disability, and subjective physical and mental function.
The reported side effects were minimal, with no reports of
dissociation or psychotic symptoms. Adverse events included
sedation (50 mg, n=3; placebo, n=1), dizziness (50 mg, n=1;
placebo, n=3), nausea/vomiting (75 mg, n=1), confusion (50 mg,
n=1), vivid dreams (placebo, n=1; 50 mg, n=1) headache (placebo,
n=1), and erythema (placebo, n=2). Ketamine blood levels were not
measured in this study.
[0116] The second study is a randomized, double-blind,
placebo-controlled trial using racemic ketamine in a transdermal
delivery system (Azevedo et al., 2003). A total of 49 women
(ketamine, n=26, placebo, n=23) were studied after abdominal
gynecological surgery in which lidocaine epidural blockade was
used. Postoperatively, 25 mg is delivered over 24 hrs in decaying
quantities (hours 1-4: 1.25 mg/hour; hours 5-8: 0.5 mg/hour; hours
9-24: 0.4 mg/hour). The outcome measure was the time to first
rescue analgesic, which was prolonged for ketamine compared to
placebo. The subjects reported no side effects from the ketamine,
such as nausea or vomiting, confusion, or hallucinations. There is
no report of the transdermal administration of ketamine for
treating treatment-resistant depression. Similarly, there is no
report of transdermal administration of ketamine for treating
treatment-resistant depression, wherein the administration is
repeated multiple times within a specific time period. For example,
the administration is administered at least twice, at least three
times, at least four times, at least five time, at least six times,
at least seven times, at least eight times, at least nine times, or
at least ten times over a period of two to three weeks.
[0117] Ketamine is formulated into pharmaceutical compositions
comprising a carrier suitable for the desired delivery method.
Exemplary carriers include, but are not limited to, any of a number
of standard pharmaceutical carriers such as sterile phosphate
buffered saline solutions, bacteriostatic water, and the like. A
variety of aqueous carriers may be used, e.g., water, buffered
water, 0.4% saline, 0.3% glycine and the like.
[0118] The compositions of the invention may be designed to be
short-acting, fast-releasing, long-acting, or sustained-releasing
as described herein. Thus, the pharmaceutical formulations may also
be formulated for controlled release or for slow release.
[0119] Specific dosages may be adjusted depending on conditions of
disease, the age, body weight, general health conditions, sex, and
diet of the subject, dose intervals, administration routes,
excretion rate, and combinations of drugs. Any of the above dosage
forms containing effective amounts are well within the bounds of
routine experimentation and therefore, well within the scope of the
instant invention.
[0120] The invention also provides a device for patient
self-administration of ketamine, which device comprises a
transdermal patch containing a ketamine formulation and a
pharmaceutically acceptable carrier, wherein the device is
formulated to disperse an amount of the ketamine formulation rhat
contains a dose of ketamine effective to alleviate depression.
[0121] Those of skill in the art are well aware of general
technologies for transdermal drug delivery or administration of a
therapeutic agent to the skin. Transdermal drug delivery offers
controlled release of a drug to the patient and transdermal patches
are user-friendly, convenient, painless, and offer multi-day dosing
which usually results in improved patient compliance. In addition,
this form of administration of ketamine in the present invention is
a particularly useful alternative to intranasal delivery as it is
less likely to lead to drug abuse as compared to an intranasal
delivery method. The methods of the invention for treating
treatment-resistant patients with a transdermal administration of
ketamine can include administering ketamine to skin of the face,
head or body. Such a ketamine composition can be administered to
the skin of the face, scalp, temporal region, arms, stomach,
thighs, back, neck and the like. Suitable skin of the face includes
skin of the chin, the upper lip, the lower lip, the forehead, the
nose, the cheek, the skin around the eyes, the upper eyelid, the
lower eyelid or combinations thereof. Suitable skin of the scalp
includes the front of the scalp, the scalp over the temporal
region, the lateral part of the scalp, or combinations thereof.
Suitable skin of the temporal region includes the temple and the
scalp over the temporal region and combinations thereof. The
ketamine may be formulated into a bioadhesive patch or a
bioadhesive strip with an occlusive covering. Alternatively, the
transdermal ketamine composition for administration to the skin can
be applied as a topical ointment, a topical gel, a lotion, a cream,
a solution, a spray, a paint, a film, a foil, a cosmetic, to be
applied to the skin in a layer with or without an occlusive
dressing.
[0122] In addition to transdermal patches, creams lotions and the
like, intradermal administration of the ketamine composition also
is contemplated. Intradermal administration of a therapeutic agent
is defined as within or between the layers of skin. In contrast,
subcutaneous administration is defined as beneath the initial layer
of skin and intravenous is a systemic administration into the
bloodstream. Administration of therapeutic agents by intradermal,
intravenous or subcutaneous injection are common means of drug
delivery by one skilled in the art.
[0123] Once a subject has been treated for depression using the
methods of the invention, he/she is monitored for depression
symptoms by conventional analysis techniques as described above and
such monitoring can be used to adjust the dosage of therapy
used.
EXAMPLE 1
[0124] The following examples are included to demonstrate certain
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventors to
function well in the practice of the invention, and thus are
considered to constitute certain aspects for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
[0125] Methods
[0126] Men and women, ages 18 to 65 years, who were inpatients with
a diagnosis of major depressive disorder recurrent without
psychotic features as diagnosed by means of the Structured Clinical
Interview for Axis I DSM-IV Disorders--Patient Version 28 were
eligible to participate. Subjects were required to have a score of
.gtoreq.18 on the 21-item Hamilton Depression rating (HDRS) [29])
at screening and at start of ketamine/placebo infusion, and to have
previously failed at least two adequate antidepressant trials
(adequacy of antidepressant trials were determined with the
Antidepressant Treatment History Form [30]).
[0127] All subjects were in good physical health as determined by
medical history, physical exam, blood labs, electrocardiogram,
chest x-ray, urinalysis and toxicology. Subjects were free of
comorbid substance abuse or dependence for at least 3 months and
judged clinically not to be a serious suicidal risk. Comorbid axis
I anxiety disorder diagnoses were permitted if they did not require
current treatment.
[0128] Forty-two subjects were screened and twenty-four subjects
were excluded as they did not meet inclusion/exclusion criteria
(n=11) or refused to participate (n=13). After a 2 week drug-free
period, 18 subjects with DSM-IV major depression were randomized to
an intravenous infusion of either ketamine hydrochloride (0.5
mg/kg) or placebo (saline solution) given over 40 minutes with a
Baxter infusion pump on 2 test days, a week apart, in a
double-blind, crossover study. Seventeen subjects received ketamine
and 14 received placebo. Four subjects did not receive placebo
after ketamine infusion because they maintained a response for more
than 7 days and one subject was discontinued from the study for
medical reasons after a placebo infusion.
[0129] Subjects were rated 60 minutes prior to the infusion and at
40, 80, 110, and 230 minutes as well as 1, 2, 3, and 7 days after
the infusion. The 21-item HDRS, Beck Depression Inventory Scale
(BDI; [31]), Brief Psychiatric Rating Scale-positive symptoms
(BPRS; [32]), Young Mania Rating Scale (YMRS; [33]), and the visual
analogue scales score (VAS-depression; [34]). Raters, who trained
together to establish reliability, performed patient ratings. High
inter-rater reliability for the HDRS (ICC=0.81) and the YMRS
(ICC=0.91) were obtained. Subjects were rated by a separate set of
raters to help maintain blind to the infusion procedures and
resulting side effects. The first set of raters administered the
scales on the day of infusion (60 minutes prior to the infusion and
40, 80, 110 post-infusion). From 230 minutes onwards (days 1
through 7), a separate group of raters rated the subjects. Clinical
response was defined as a 50% or greater decrease in the HDRS
rating scale from baseline and remission as HDRS.ltoreq.7 [35].
[0130] A full factorial, fixed effects linear mixed model with a
compound symmetry covariance structure was used to examine the
differences between ketamine and placebo over 9 time points from
baseline to 7 days. Restricted maximum likelihood estimation was
used to estimate missing values. Significant effects were examined
with simple effects tests. The 21-item HDRS was the primary outcome
measure. Scores from the BDI, BPRS, YMRS, and VAS were secondary
outcome measures. Secondary analysis included examination of the
individual items of the HDRS. Significance was evaluated at
.alpha.<0.05, two-tailed. Following Shapiro-Wilk's test and
visual examination of the data, no cells deviated substantially
from normality.
[0131] Three sets of linear mixed models were run to fully
understand the influence of the active treatment. One set of
analysis included only those who completed both phases of the study
(completers analysis). Subjects who did not receive both treatment
conditions were not included in this analysis. A second set
included all available data (intent to treat analysis). Since
ratings were made for each day regardless of whether the
participants continued in the study, the placebo ratings for the
ketamine drop outs appeared to be much lower than would have been
expected in an actual placebo phase. A third set of statistics was
performed on the first test condition only. In this case the drug
effect was a between subjects factor instead of a within subjects
factor. Secondary analysis on individual items was performed only
with completers.
[0132] To evaluate the proportion of responders and remitters at
each time point, a McNemar test was used at each time point for the
completers and the results were Bonferroni corrected for the number
of time points examined.
[0133] Carryover was examined using a linear mixed model with the
same structures as the primary analysis where drug was a within
subjects factor, treatment order was a between subjects factor, and
only the baseline measure for each phase was used. The intent to
treat sample was used for this analysis since baseline data for
both phases was available.
[0134] Results
[0135] Subject's demographic and clinical characteristics are
summarized in Table 1. There were 12 females, and 6 males, and the
mean age was 46.7.+-.11.2. Sixty-one percent and 61% had a lifetime
comorbid anxiety diagnosis, 39% a lifetime diagnosis of any
substance abuse or dependence and 28% a lifetime diagnosis of
alcohol abuse or dependence. The mean length of illness was 23.7
years.+-.12.5, the mean duration of the current depressive episode
was 33.6 months.+-.37.4, and the mean number of lifetime episodes
of depression was 6.6.+-.4.7. The mean number of lifetime
antidepressant trials (not including augmentation trials) was
5.7.+-.3.4 and 4 subjects had previously received ECT. All subjects
except for one had failed an adequate antidepressant trial for the
current major depressive episode.
[0136] Using only those who completed both phases of the study, the
linear mixed model with the HDRS showed significant main effects
for drug (F=58.24, df=1,203, p<0.0001) and time (F=9.48,
df=8,203, p<0.0001) and an interaction between drug and time
(F=4.15, df=8,203, p<0.001). Simple effects tests indicated
significant improvement on ketamine over placebo at 110 minutes
through 7 days. The effect size for the drug difference was very
large (d=1.46, 95% C.I. 0.91-2.01) after 24 hours and moderate to
large (d=0.68, 95% C.I. 0.13-1.23) after 1 week. The percent change
in HDRS scores from baseline to day 1 for each subject is listed on
Table 1. FIG. 2 shows the generalized least squares means and
standard errors for the completer analysis. The intent to treat
analysis had similar effects (drug: F=34.08, df=1,260, p<0.0001;
time: F=8.92, df=8,257, p<0.0001; drug x time: F=5.29, df=8,257,
p<0.0001). Notably, participants were better than placebo within
2 hours (110 minutes) and remained better through 7 days (FIG.
2).
[0137] Looking at possible carryover effects with the intent to
treat sample, a linear mixed model looking at the baseline measures
showed a significant main effect for drug (F=6.25, df=1,16, p=0.02)
and a significant interaction (F=5.05, df=1,16, p=0.04), but no
main effect for order (F=1.54, df=1,16, p=0.23). Participants who
received placebo first had similar baseline measures for the first
and second phases (24.4.+-.6.9 vs. 24.9.+-.6.8) (F=0.03, df=1,16,
p=0.86), but those who received ketamine first had much lower
baselines in the second phase (24.9.+-.6.9 vs. 17.2.+-.6.9)
(F=11.80, df=15, p=0.004).
[0138] To examine data relatively independent of carryover effects,
only the first phase data was used in an additional analysis.
Results were similar to those of the completers and intent to treat
analysis. There were significant main effects for drug (F=10.44,
df=1,16, p=0.005) and time (F=8.25, df=8,126, p<0.0001) and a
significant interaction between drug and time (F=4.66, df=1,126,
p<0.0001). Scores were lower on ketamine by 80 minutes and the
difference remained significant through the seventh day.
[0139] Using the completers with the BDI, there were significant
main effects for drug (F=50.57, df=1,200, p<0.0001) and time
(F=5.82, df=8,200, p<0.0001) and a trend level interaction
between drug and time (F=1.90, df=8,200, p=0.06). The patient
ratings showed that ketamine seemed to improve depression at 40
minutes through 7 days. Additionally, there were significant
changes in the VAS depression scores (drug: F=59.88, df=1,198,
p<0.0001; time: F=4.70, df=8,198, p<0.0001; drug x time:
F=1.92, df=8,198, p=0.058). Similar to BDI, ketamine improved mood
at 40 minutes through 7 days.
[0140] On the individual HDRS symptoms, 7 of 20 symptoms had
significant time by drug interactions; loss of insight was not
tested since none of the participants had this symptom. Depressed
mood, guilt, work and interests, and psychic anxiety improved
significantly. The earliest improvements were at 40 minutes for
depressed mood and guilt. Depersonalization or derealization was
worse from 40 to 110 minutes. Motor retardation and
gastrointestinal symptoms were worse at 40 minutes, but at day 1
motor retardation was better on ketamine than on placebo. An
additional 7 symptoms showed only a significant main effect for
drug; symptoms improved on ketamine for suicide, insomnia, general
somatic symptoms, genital symptoms, and hypochondriasis. At
baseline, no symptoms were different between the ketamine and
placebo phases.
[0141] FIG. 3 shows the proportion of responders (FIG. 3A) and
remitters (FIG. 3B) at each time point for the intent to treat
sample. One day after infusion 12 of the 17 (71%) subjects treated
with ketamine met response criteria as compared to 0 of 14 (0%) on
placebo. Five of 17 (29%) on ketamine met remission criteria one
day after infusion, while none (0%) reached remission on placebo at
the same time point. Six (35%) subjects maintained response to
ketamine for at least 1 week; 2 of these maintained response at
least 2 weeks. By contrast, no subject on placebo responded at 1 or
7 days. For completers, McNemar tests showed significantly more
responders to ketamine on day 1 and 2, but after Bonferroni
correction, only day 1 was significant. The number of remitters was
not significant at any time point.
[0142] BPRS positive symptoms [35, 34] were worse on ketamine than
placebo only at 40 minutes (drug: F=4.23, df=1,200, p=0.04; time:
F=9.31, df=8,200, p<0.0001; drug x time: F=6.89, df=8,200,
p<0.0001) (FIG. 2). Similarly, YMRS scores were worse (higher
score) on ketamine than placebo at 40 minutes only, but they were
significantly better from days 1 to 2 (drug: F=3.08, df=1,201,
p=0.08; time: F=3.54, df=8,201, p<0.001; drug x time: F=4.68,
df=8,201, p<0.0001) (FIG. 2).
[0143] There was a trend for an inverse relationship between the
percent change in HDRS at day 1 and the peak percent change in BPRS
positive symptoms (r=-0.46, p=0.06). None of the other factors
listed in table 1 predicted a response to ketamine.
[0144] Adverse Events: Side effects occurring more commonly on
ketamine than placebo were perceptual disturbances, confusion,
elevations in blood pressure, euphoria, dizziness, and increased
libido. Side effects occurring more frequently with placebo than
ketamine were gastrointestinal distress, increased thirst,
headache, metallic taste, and constipation. The majority of these
side effects ceased within 80 minutes after the infusion. In no
case did euphoria or derealization/depersonalization persist beyond
110 minutes (FIG. 2). No serious adverse events occurred during the
study.
[0145] Discussion
[0146] The present invention provides a robust, rapid (hours) and
relatively sustained (1 week) response to a single-dose of the NMDA
antagonist ketamine. Improvement in mood ratings for the course of
the week was greater with ketamine than placebo; this difference
was statistically significant for the 21-HDRS (from 110 minutes
through 7 days) and self-rated BDI (from 40 minutes through 7
days). To our knowledge, there has never been a report of any other
drug or somatic treatment (i.e., sleep deprivation,
thyrotropin-releasing hormone, antidepressant, dexamethasone, or
electroconvulsive therapy [ECT]) [36, 39, 40, 41, 42] that results
in such a dramatic rapid and prolonged response with a single
administration. In reviews of antidepressant trials in major
depression response rates at week 8 were for bupropion 62%, SSRI
63%, and venlafaxine 65% [37, 38, 42]. In the present study
involving treatment-resistant subjects, these response rates were
obtained the day after the ketamine infusion.
[0147] In contrast to the dramatic effects observed in this study,
a previous controlled study did not show the low- to
moderate-affinity non-competitive NMDA antagonist memantine,
administered orally, to have antidepressants effects [63, 38].
While it is likely that higher affinity NMDA antagonists are
necessary for antidepressant effects to occur, it must be
acknowledged that the intravenous administration may also be an
important factor.
[0148] It is possible that higher affinity NMDA antagonists are
necessary to induce antidepressant effects. Ketamine in contrast to
memantine has (a) higher affinity for the NMDA receptor, (b) much
slower open channel blocking/unblocking kinetics, (c), a different
type of channel closure (i.e., `trapping block` as opposed to
`partial trapping` properties), [44, 63] and (d) different NMDA
subunit selectivity [64, 65, 66]. Such differences might explain
the antidepressant properties observed with ketamine in the present
trial.
[0149] When comparing our results with the preliminary study by
Berman et al., [27] we confirmed the finding of rapid
antidepressant response with ketamine. The larger sample size of
our study permitted us to obtain additional information regarding
the time of onset, course of response and degree of improvement
with ketamine. Compared to the previous study, we were able to (a)
detect an earlier onset of antidepressant effect (110 minutes by
objective ratings and 40 minutes by self-report, post-infusion vs.
230 minutes) after infusion; (b) find a more prolonged
antidepressant effect of ketamine which remained significant up to
7 days post-infusion (the previous study collected ratings only
until day 3); and (c) better characterize the magnitude of response
and remission obtained over the course of 7 days. The Berman et
al., study group reported that 4 of 8 patients obtained a 50% or
greater decreases in HDRS during the 3-day follow-up period. In our
study, we found 71% response and 29% remission rates on day 1
(FIGS. 2, 3) and 35% of subjects were able to maintain response for
at least 1 week. The relatively prolonged antidepressant effect
that occurred with ketamine (.about.1 week) is remarkable
considering its short half-life which is approximately 2 hours for
ketamine [67] and 5 hours for norketamine; the latter metabolite is
7-10 times less potent than ketamine [68]. Blood levels of ketamine
or its metabolites were not collected in this study. As a result,
this study cannot rule out the possibility that differences in drug
metabolism may have contributed in part to the current
findings.
[0150] It should be noted that although these results are
provocative, they may not be generalizable to all depressed
populations. The subjects in this study were a refractory subgroup
who were relatively late in their course of illness (Table 1), and
as such, their neurobiology and pharmacological responses may be
different from those with a less severe or shorter course of
illness.
[0151] Several factors need to be considered in interpreting these
data. Although the sample size was relatively small, three
different types of analysis showed significance of ketamine over
placebo, and the effect sizes of this study were very large at day
1 and moderate to large at day 7. Consistent with all of the
published randomized placebo-controlled studies with ketamine, we
also found short-lived perceptual disturbances [26, 27, 44, 45, 46,
64]; it has to be acknowledged that such symptoms could have
affected study blind. Hence, limitations in preserving study blind
may have biased patient reporting by diminishing placebo effects,
thereby potentially confounding results. One potential study design
in future studies with ketamine might be to include an active
comparator such as intravenous amphetamine (a dopamine agonist)
which also produces psychotogenic effects [77].
[0152] However, the time of onset and course of antidepressant
response (relatively prolonged) after receiving only one dose of
ketamine was nearly identical for each subject; this pattern
suggests that there was indeed, a true drug effect. The improvement
associated with ketamine infusion reflects a lessening of core
symptoms of depression and is disconnected from ketamine-induced
euphoria and psychotomimetic symptoms. In support, the
antidepressant effect of ketamine became significant in the HDRS
scale at 110 minutes after a return of BPRS positive and YMRS
scores to baseline (FIG. 2). However, although BPRS positive scores
returned to baseline within 110 minutes, the change in BPRS
positive symptoms from baseline to the 110 minute time point
trended to predict a greater percent change (decrease) in HDRS
scores at day 1. As a result, future research should explore a
wider range of ketamine doses and rates of administration, and
determine if the presence or intensity of euphoric or psychomimetic
effects are necessary for rapid antidepressant effects to occur.
The dose of 0.5 mg/kg chosen for the present study is reported to
be sufficient to test the validity of the concept of the NMDA
receptor antagonism with ketamine. The dose of ketamine used in our
study was based on 1) in vitro data of NMDA blockade, 2) its mood
enhancing effects in healthy volunteers and 3) its antidepressant
effects in a pilot study of patients with major depression [27,
46].
[0153] While ketamine is believed to be relatively selective for
NMDA receptors, the possibility that these intriguing results are
mediated by interactions with other receptors cannot entirely be
ruled out [65,69]. However, ketamine binds to the NMDA receptor
with an affinity that is several fold higher than that for other
sites, [70, 71, 72, 73] and behaviors induced by NMDA receptor
antagonists are not blocked by opiate, cholinergic, or monoamine
receptor antagonists [74], providing indirect evidence that
ketamine's behavioral effects are mediated by its interaction with
the phenylcyclidine (PCP) site. In vitro studies have found that
ketamine only reduces non-NMDA voltage-gated potassium currents at
much higher than reported in patients anesthetized with ketamine
[75]. This suggests that low doses of ketamine enhance selectivity
for the PCP site. Nevertheless, more selective NMDA antagonists
will need to be tested in patients with major depression. Several
NR2B subunit-selective antagonists are currently being developed
for ischemic brain injury [76].
[0154] In conclusion, the results of the present study support the
hypothesis that directly targeting the NMDA receptor complex may
bring about rapid and relatively sustained antidepressant effects.
This line of research suggests a novel avenue holds considerable
promise for developing new treatments for depression that have the
potential to alleviate much of the morbidity and mortality
associated with the delayed onset of action of traditional
antidepressants. Those of skill can now use the studies described
herein to develop strategies for maintaining the rapid
antidepressant response obtained with ketamine in long-term
therapy.
EXAMPLE 2
Repeated Administration of a Fixed Dose IV Ketamine
[0155] The following example describes a treatment strategy for
treatment-resistant depression involving the repeated
administration of ketamine for rapid mood stabilization.
[0156] A fixed IV ketamine dose (0.5 mg/kg infusion over 40
minutes) is repeated for up to six to nine sessions over a two to
three week period in hospital. The determination of the number of
treatment sessions is based on clinical response and tolerability.
Standard pharmacotherapy treatments would be initiated in hospital
such that once the final ketamine treatment session is completed;
the patient has achieved a therapeutic dosage of an antidepressant
for relapse prevention.
EXAMPLE 3
Repeated Administration of a Continuation Dose of IV Ketamine
[0157] The following example describes another treatment strategy
for treatment-resistant depression involving the repeated
administration of a continuation dose of ketamine for rapid mood
stabilization.
[0158] All patients would initiate IV ketamine at the dose of 0.5
mg/kg at a rate of 1 mg/min, with continued titration over 40
minutes based on tolerability. At the first treatment, a
tolerability threshold is determined using an empirical titration
procedure based on the presence of psychotic side effects. he
individualized optimal tolerated dose would serve as the
continuation dosage for repeated treatments as described in Example
2 above. For patients who respond to IV ketamine at the 24 hour
assessment, the continuation dose would be 20% reduced from the
dose associated with psychotic side effects. If a patient did not
have any psychotic side effects and is a responder at 24 hours,
then the standard dose of 0.5 mg/kg is continued for the repeated
dose phase.
EXAMPLE 4
Transdermal Administration of Ketamine
[0159] The following example describes treatment strategies for
treatment-resistant depression involving transdermal administration
of ketamine for rapid mood stabilization.
[0160] Another potential route of administration of ketamine is the
use of a transdermal patch. Patients would be given a patch
comprising a reasonable starting dose for depression as described
in Azevedo et al 2003 (25 mg patch over 24 hours). For repeated
dosing administration, a patch will be administered six-nine times
over a two to three week period. The determination of the number of
treatment sessions is based on clinical response and
tolerability.
[0161] All of the above U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non patent publications referred to in this
specification and/or listed in the Application Data Sheet, are
incorporated herein by reference, in their entirety.
[0162] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
TABLE-US-00001 TABLE 1 Demographic, and Clinical Characteristics
Current Number of Failed Length of Episode, previous medication and
Number Age, yrs Gender illness, yrs mo episodes somatic treatments
1 43 F 24 4 10 SSRI (2); MAOI; AAP (2); BZD (3) 2 46 M 29 144 2
SSRI (3); SNRI; Bup; OAD (4) AAP; Lam; Sti; BZD 3 35 F 20 11 20
SSRI; Bup; TCA; OAD (2); AAP; Lam; BZD(3) 4 43 F 24 24 4 SSRI (3);
SNRI; Bup; OAD (2); Li; Lam; Sti (2) 5 45 F 27 9 1 SSRI (3); BZD 6
56 F 38 24 10 SSRI (3); Bup; TCA (2); VPA; BZD (2) 7 57 F 44 60 9
SSRI (3); Bup MAOI; OAD (2); AAP (3); Li; Lam; Sti; BZD (3); ECT 8
19 F 3 8 4 SSRI (3); Bup; Sti 9 48 F 33 60 9 SSRI (4); Bup; OAD;
VPA; Sti; BZD 10 45 M 14 1 6 SSRI (4); TCA; OAD (3); Sti; BZD (3);
ECT 11 28 M 16 17 4 SSRI (2); SNRI; TCA; OAD; AAP (2); Li; Lam; BZD
(3) 12 46 F 13 4 9 SSRI (2); Bup; TCA (2) 13 55 M 22 4 9 SSRI (2);
Bup; AAP; Li; BZD; (2) 14 62 F 6 12 4 SSRI (3); OAD (2); BZD 15 60
F 47 55 3 SSRI (2); TCA; BZD (2) 16 59 M 7 84 3 SSRI (2) 17 50 M 31
60 3 SSRI (4); Bup; TCA (3); MAOI; OAD (7); VPA; Sti (3); BZD; AAP;
Li; ECT 18 44 F 29 24 10 SSRI; SNRI; TCA; OAD; AAP; Sti; ECT Group
46.7 .+-. 11.2 12 F/6 M 23.7 .+-. 12.5 33.6 .+-. 37.4 6.6 .+-. 4.7
5.7 .+-. 3.4*.dagger. Lifetime Peak change diagnosis of Lifetime in
BPRS any diagnosis of positive substance alcohol abuse symptoms %
Change in HDRS abuse or or on (day 1) Number dependence# dependence
Ketamine Ketamine Placebo 1 No No +9 -90% N/A 2 No No +2 -85% -15%
3 Yes No +5 -78% N/A 4 No No +7 -78% +11% 5 Yes Yes -1 -74% +14% 6
Yes Yes +7 -64% -18% 7 Yes Yes +3 -61% 0% 8 No No 0 -57% -27% 9 Yes
No +8 -55% N/A 10 Yes Yes +2 -54% +25% I1 No No -1 -50% -41% 12 No
No +6 -50% 0% 13 No No -2 39% N/A 14 No No +3 -39% -10% 15 No No +1
-36% -26% 16 No No +3 -29% -35% 17 No No +1 -17% -20% 18 Yes Yes
N/A N/A +8% Group 7 Yes/11 No 5 Yes/13 No +3.1 .+-. 3.4 -56.2 .+-.
20.4% -9.8 .+-. 20.1% Abbreviations: AAP, atypical antipsychotic:
BZD, benzodiazepine; Bup, buproprion; ECT; electroconvulsive
therapy; HDRS, Hamilton depression rating scale; Lam, lamictal; Li,
lithium; MAOI, monoamine oxidase inhibitor; OAD, other
antidepressants (e.g. nefazodone, trazodone, pramipexole, etc):
SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective
serotonin reuptake inhibitor; TCA, tricyclic antidepressants; VPA,
depakote; Sti, stimulant; #lifetime substance abuse/column also
includes subjects with lifetime alcohol abuse/dependence; *number
of antidepressant trials not including augmentation strategies;
.dagger.All subjects except for one had failed an adequate
antidepressant trial for the current depressive episode; "-"
indicates a decrease in HDRS scores (improvement of depression) and
"+" indicates an increase in HDRS scores (worsening of
depression).
[0163] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of specific
embodiments, it will be apparent to those of skill in the art that
variations of the compositions and/or methods and in the steps or
in the sequence of steps of the method described herein can be made
without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and physiologically related may be
substituted for the agents described herein while the same or
similar results are achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims.
[0164] The references cited herein throughout, to the extent that
they provide exemplary procedural or other details supplementary to
those set forth herein, are all specifically incorporated herein by
reference. At certain points throughout the specification,
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