Methods for the treatment of mood disorders
United States Patent: 7,884,077
Issued: February 8, 2011
Inventors: Cohen; Bruce M.
(Lexington, MA), Murphy; Beth L. (Arlington, MA)
Assignee: The McLean
Hospital Corporation (Belmont, MA)
Appl. No.: 12/229,841
Filed: August 27, 2008
Pharm Bus Intell
& Healthcare Studies
The invention features methods of
treating mood disorders, such as manic disorders, and stabilizing moods by
administering a kappa agonist or partial agonist to a subject in need
Description of the
BACKGROUND OF THE INVENTION
The invention relates to the treatment of mood disorders.
Opiates have a long history of treating mood disorders. In the classical
world, records indicate that opium was used as a treatment for both
`melancholia` and `mania` (Weber et al., Int. Clin. Psychopharmacol.
3:255-266 (1988)). It has also been long noted that opiates can have
euphorigenic effects. However, as awareness of opiate addiction increased,
the use of potentially-addicting opiate treatment for mood disorders fell
out of favor. Interest in opiates as treatments for mood disorders has
increased again, as a better understanding of opiate receptor subtypes and
their individual involvement in mood and addiction developed.
As in many other neurotransmitter systems, the opiate system involves
multiple receptor subtypes. Three kinds of opioid receptors have been
identified; mu, kappa, and delta. The best-studied of these receptors are
the mu receptors, which are preferentially bound by morphine and related
compounds. The endogenous ligands for these receptors are endorphins. Mu
receptors are concentrated in regions which mediate analgesic pathways.
These receptors are also located in regions which are critical for the
reinforcing effects of opiates. Kappa opiate receptors (KOR) are also
found in areas mediating addiction and reward. In contrast to many
opiate-receptor agonists, activation of KOR is not highly addictive, and
co-administration may decrease the addictive potential of other substances
(Shippenberg et al., Ann N Y Acad Sci. 937:50-73 (2001)). The endogenous
ligand for KOR is dynorphin.
As their location would suggest, studies indicate that mood and reward
systems are modulated by the opiate systems (see Todtenkopf et al.,
Psychopharmacology 172:463-470 (2004) and Pickar et al., Biol. Psychiatry
17:1243-1276 (1982)). Changes in cAMP response element binding protein (CREB)
appear to mediate mood and affect animal models of reward and depression (Pliakas
et al., J. Neurosci. 21:7397-7403 (2001)). Interestingly, CREB modulates
the expression of dynorphin, an endogenous ligand of KOR (see Todtenkopf
et al., Psychopharmacology 172:463-470 (2004) and Carlezon et al., Science
Therapeutic alternatives for bipolar mania include mood stabilizers such
as valproic acid, lithium, and carbamezapine. Alternatives also include
neuroleptics such as haldol, trilafon, thorazine, zyprexa, risperdal,
seroquel, and clozaril. In addition, benzodiazepines and
electro-convulsive treatment may be used to treat bipolar mania.
Neuroloeptics have been shown to increase the activity of neurons which
produce dynorphin (Ma et al, Neuroscience 121:991-998 (2003)).
There is a need for new therapies for the treatment of mood disorders,
such as bipolar mania, which provide a more rapid amelioration of manic
symptoms. The profile and actions of the kappa opioid system make drugs
that target this system particularly promising as a treatment modality,
with relatively low risk of addictive properties.
SUMMARY OF THE INVENTION
The invention is based on the discovery that modulation of activity at
kappa opioid receptors can be useful for the treatment of mood disorders.
For example, compounds exhibiting agonist or partial agonist activity at
kappa receptors can be useful for the treatment of bipolar disorder, e.g.,
as mood stabilizers, and for the treatment of the manic phase of bipolar
disorder, among other conditions.
In a first aspect, the invention features a method for treating mania in a
human subject in need thereof by administering an effective amount of a
kappa receptor agonist or partial agonist. Kappa receptor agonists and
partial agonists can be particularly useful for treating mania associated
with bipolar disorder, acute mania, and chronic mania. The mania can occur
in a single episode or be recurring.
The invention further features a method for treating bipolar disorder in a
human subject in need thereof by administering an effective amount of a
kappa receptor agonist or partial agonist.
The invention also features a method for stabilizing the mood of a human
subject diagnosed with a mood disorder by administering an effective
amount of a kappa receptor partial agonist.
The invention further features a kit comprising (i) a compound having
kappa receptor agonist or partial agonist activity, and (ii) instructions
for the administration of the compound for the treatment of mania.
The invention also features a kit comprising (i) a compound having kappa
receptor agonist or partial agonist activity, and (ii) instructions for
the administration of the compound for the treatment of bipolar disorder.
The invention further features a kit comprising (i) a compound having
kappa receptor agonist or partial agonist activity, and (ii) instructions
for the administration of the compound for stabilizing the mood of a
For any of the above methods and kits of the invention the kappa receptor
agonist or partial agonist can be selected from dynorphin A 1-17,
ethylketocyclazocine, U50,488H, tifluadom, .beta.-funaltrexamine,
nalmefine, nalorphine, pentazocine, and substantially pure enantiomers
thereof. Desirably, the kappa receptor agonist or partial agonist is
pentazocine, either administered as a racemate, or as a substantially pure
enantiomer as (-) pentazocine or (+) pentazocine.
The kappa receptor partial agonists and full agonists can be administered
systemically, including, for example, by intravenous, intramuscular, or
subcutaneous injection, orally, or by topical or transdermal application,
provided that the agent is capable of penetrating the blood-brain barrier
sufficiently to be effective. Alternatively, the kappa-selective compounds
can be centrally administered using, for example, by an intrathecal,
intracerebroventricular, or intraparenchemal injection.
By "kappa receptor partial agonist" is meant any chemical compound which
has affinity for the kappa opioid receptor and agonist activity, but
produces only a partial (i.e., submaximal) response of between 15% and 85%
in comparison to dynorphin A, an endogenous neurotransmitter of the kappa
By "kappa receptor agonist" (KOR) is meant any chemical compound which has
affinity for the kappa opioid receptor and agonist activity, and produces
at least 85% of the maximal response in comparison to dynorphin A, an
endogenous neurotransmitter of the kappa opioid receptor.
The term "administration" or "administering" refers to a method of giving
a dosage of a pharmaceutical composition to a patient, where the method
is, e.g., topical, transdermal, oral, intravenous, intraperitoneal,
intracerebroventricular, intrathecal, or intramuscular. The preferred
method of administration can vary depending on various factors, e.g., the
components of the pharmaceutical composition, site of administration, and
severity of the symptoms being treated.
By "effective amount" is meant an amount of a compound of the invention
which has a therapeutic effect, e.g., which prevents, reduces, or
eliminates the mania, or mood fluctuations. This amount, an effective
amount, can be routinely determined by one of skill in the art, by animal
testing and/or clinical testing, and will vary, depending on several
factors, such as the particular disorder to be treated and the particular
compound of the invention used. This amount can further depend upon the
subject's weight, sex, age and medical history.
As used herein, the term "substantially pure" refers to a composition
containing a single predominant isomer of a kappa receptor partial agonist
or full agonist possessing one or more chiral centers, wherein the amount
of any other single isomer (i.e., enantiomer or diastereomer) of the
predominant isomer is less than 1%, 0.5%, 0.1%, 0.05%, or even 0.01% of
the mass of the predominant isomer present in the composition.
The invention features methods of treating mood disorders, such as manic
disorders, and stabilizing moods by administering a kappa agonist or
partial agonist to a subject in need thereof.
Compounds can be assayed to determine whether they have affinity and
efficacy for kappa receptors, and thus are useful in the methods of the
To determine their affinity for specific opioid receptors, the compounds
described herein can be characterized in radioligand receptor binding
assays, using ligands that are specific for the mu, delta and kappa
receptors. For example, the binding assays may utilize guinea pig brain
membranes or stably transfected Chinese Hamster Ovary (CHO) cells
expressing each of the three opioid receptors, as described in Example 1.
To determine their efficacy (e.g., agonist, partial agonist, antagonist)
at a specific opioid receptor, compounds can be characterized by
[.sup.35S]GTP.gamma.S binding assay, as described in Example 2.
Mania-like symptoms can be induced in rodents by the administration of
psychomotor stimulant drugs such as cocaine or amphetamine.
Psychostimulants produce a range of behaviors in animals that appear
similar to mania, including hyperactivity, heightened sensory awareness
and alertness, and changes in sleep patterns. Psychostimulant--induced
hyperactivity is mediated by increased dopaminergic transmission in
striatal regions. Based on this information, psychostimulant--induced
hyperactivity in rodents has become a standard model for the screening of
antimanic drugs. The mania-like effects of these psychomotor stimulants
can be studied in behavioral assays that quantify locomotor activity
("open field activity") or the function of brain reward systems ("place
conditioning" or "intracranial self-stimulation" (ICSS)) (see Example 3).
The antimanic-like effects of a compound can be identified by its ability
to reduce, attenuate, or block the stimulant or rewarding effects of
cocaine or amphetamine in these assays. For further details see, for
example, Einat and Belmaker Animal models of bipolar disorder: From a
single episode to progressive cycling models; In: "Contemporary Issues in
Modeling Psychopathology" Myslobodsky M, Weiner I (Eds.), 2000; London:
Kluver Academic, New York, pp 165-179.
Kappa agonists and partial agonists can be administered for the treatment
of any psychologic or psychiatric disorder having symptoms that include
abnormalities of mood or emotion, which are amenable to treatment
according to the present methods. For example, kappa agonists and partial
agonists can be administered to treat disorders of mood, including,
without limitation, Bipolar Disorder, Schizoaffective Disorder,
Schizophrenia and other psychotic disorders, Anxiety Disorders, Panic
Disorder, Traumatic Stress Disorders, Phobic Disorders, and Personality
Disorders with abnormal mood, such as Borderline Personality Disorder,
Schizoid and Schizotypal Disorders. For example, compounds having partial
agonist activity at kappa opioid receptors are useful as mood stabilizers
for the treatment of, for example, bipolar disorder; and compounds having
agonist activity at kappa opioid receptors are useful for the treatment of
Using the methods of the invention, kappa agonists or partial agonists may
be administered with a pharmaceutically acceptable diluent, carrier, or
excipient, in unit dosage form. Administration may be transdermal,
parenteral, intravenous, intra-arterial, subcutaneous, intramuscular,
intracranial, intraorbital, ophthalmic, intraventricular, intracapsular,
intraspinal, intracisternal, intraperitoneal, intracerebroventricular,
intrathecal, intranasal, aerosol, by suppositories, or oral
Therapeutic formulations may be in the form of liquid solutions or
suspensions; for oral administration, formulations may be in the form of
tablets or capsules; and for intranasal formulations, in the form of
powders, nasal drops, or aerosols.
Methods well known in the art for making formulations are found, for
example, in "Remington: The Science and Practice of Pharmacy" (20th ed.,
ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins). Formulations for
parenteral administration may, for example, contain excipients, sterile
water, or saline, polyalkylene glycols such as polyethylene glycol, oils
of vegetable origin, or hydrogenated napthalenes. Biocompatible,
biodegradable lactide polymer, lactide/glycolide copolymer, or
polyoxyethylene-polyoxypropylene copolymers may be used to control the
release of the compounds. Nanoparticulate formulations (e.g.,
biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be
used to control the biodistribution of the compounds. Other potentially
useful parenteral delivery systems include ethylene-vinyl acetate
copolymer particles, osmotic pumps, implantable infusion systems, and
liposomes. Formulations for inhalation may contain excipients, for
example, lactose, or may be aqueous solutions containing, for example,
polyoxyethylene-9-lauryl ether, glycolate and deoxycholate, or may be oily
solutions for administration in the form of nasal drops, or as a gel. The
concentration of the compound in the formulation will vary depending upon
a number of factors, including the dosage of the drug to be administered,
and the route of administration.
The kappa agonist or partial agonist may be optionally administered as a
pharmaceutically acceptable salt, such as non-toxic acid addition salts or
metal complexes that are commonly used in the pharmaceutical industry.
Examples of acid addition salts include organic acids such as acetic,
lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic,
palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic,
or trifluoroacetic acids or the like; polymeric acids such as tannic acid,
carboxymethyl cellulose, or the like; and inorganic acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or
the like. Metal complexes include calcium, zinc, iron, and the like.
Administration of compounds in controlled release formulations is useful
where the compound of formula I has (i) a narrow therapeutic index (e.g.,
the difference between the plasma concentration leading to harmful side
effects or toxic reactions and the plasma concentration leading to a
therapeutic effect is small; generally, the therapeutic index, TI, is
defined as the ratio of median lethal dose (LD50) to median effective dose
(ED50)); (ii) a narrow absorption window in the gastro-intestinal tract;
or (iii) a short biological half-life, so that frequent dosing during a
day is required in order to sustain the plasma level at a therapeutic
Many strategies can be pursued to obtain controlled release in which the
rate of release outweighs the rate of metabolism of the therapeutic
compound. For example, controlled release can be obtained by the
appropriate selection of formulation parameters and ingredients,
including, e.g., appropriate controlled release compositions and coatings.
Examples include single or multiple unit tablet or capsule compositions,
oil solutions, suspensions, emulsions, microcapsules, microspheres,
nanoparticles, patches, and liposomes.
Formulations for oral use include tablets containing the active
ingredient(s) in a mixture with non-toxic pharmaceutically acceptable
excipients. These excipients may be, for example, inert diluents or
fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and
antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid,
silicas, hydrogenated vegetable oils, or talc).
Formulations for oral use may also be provided as chewable tablets, or as
hard gelatin capsules wherein the active ingredient is mixed with an inert
solid diluent, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium.
The formulations can be administered to patients in therapeutically
effective amounts. For example, an amount is administered which prevents,
reduces, or eliminates the mania or mood fluctuations. Typical dose ranges
are from about 0.001 .mu.g/kg to about 2 mg/kg of body weight per day.
Desirably, a dose of between 0.001 .mu.g/kg and 1 mg/kg of body weight, or
0.005 .mu.g/kg and 0.5 mg/kg of body weight, is administered. The
exemplary dosage of drug to be administered is likely to depend on such
variables as the type and extent of the condition, the overall health
status of the particular patient, the formulation of the compound, and its
route of administration. Standard clinical trials may be used to optimize
the dose and dosing frequency for any particular compound.
The following examples are put forth so as to provide those of ordinary
skill in the art with a complete disclosure and description of how the
methods and compounds claimed herein are performed, made, and evaluated,
and are intended to be purely exemplary of the invention and are not
intended to limit the scope of what the inventors regard as their
Radioligand Binding Assays
Compounds can be characterized in radioligand receptor binding assays,
using ligands that are specific for the mu, delta and kappa receptors. The
binding assays may utilize guinea pig brain membranes or stably
transfected Chinese Hamster Ovary (CHO) cells expressing each of the three
opioid receptors. Membranes can be isolated from CHO cells that stably
express either the human mu, delta or kappa opioid receptors. At
approximately 80% confluence, the cells are harvested by the use of a cell
scraper. The cells and media from the plates are centrifuged at
200.times.g for 10 mm at 4.degree. C.; resuspended in 50 mM Tris-HCl, pH
7.5; homogenized by the use of a Polytron; centrifuged at 48,000.times.g
for 20 mm at 4.degree. C.; and resuspended in 50 mM Tris-HCl, pH 7.5, at a
protein concentration of 5-10 mg/ml, as determined by the Bradford method.
The membranes are stored frozen, at -80.degree. C. until use.
Cell membranes are incubated at 25.degree. C. with the radiolabeled
ligands in a final volume of 1 ml of 50 mM Tris-HCl, pH 7.5. Incubation
times of 60 minutes are used for the mu-selective peptide [.sup.3H]DAMGO
and the kappa-selective ligand [.sup.3H]Diprenorphine, and 4 hours of
incubation for the delta-selective antagonist [.sup.3H]naltrindole.
Nonspecific binding is measured by inclusion of 1 .mu.M naloxone. The
binding can be terminated by filtering the samples through Schleicher &
Scheull No. 32 glass fiber filters using a Brandel 48-well cell harvester.
The filters are subsequently washed three times with 3 mL of cold 50 mM
Tris-HCl, pH 7.5, and can be counted in 2 ml of Ecoscint A scintillation
fluid. For [.sup.3H]Diprenorphine binding, the filters are soaked in 0.1%
polyethylenimine for at least 30 minutes before use. IC.sub.50 values can
be calculated by a least squares fit to a logarithm-probit analysis. Ki
values of unlabeled compounds are calculated from the equation Ki=(IC.sub.50)/1=S
where S=(concentration of radioligand)/(Kd of radioligand). Cheng and
Prusoff, Biochem. Pharmacol. 22:3099 (1973). Alternatively, guinea pig
brain membranes can be prepared and used as previously described in
Neumeyer, et al., J. Med. Chem. 43:114 (2000). For further details see
Huang et al., J. Pharmacol. Exp. Ther. 297:688 (2001); and Zhu et al., J.
Pharmacol. Exp. Ther. 282:676 (1997). Other buffers may be used in the
[.sup.35S]GTP.gamma.S Binding Assays
Membranes from the CHO cell lines, expressing either the mu, delta or
kappa receptor, are incubated with 12 concentrations of each compound for
60 minutes at 30.degree. C. in a final volume of 0.5 ml of assay buffer
(50 mM Tris-HCl, 3 mM MgCl.sub.2, 0.2 mM EGTA, 100 mM NaCl, pH 7.5)
containing 3 .mu.M GDP and 0.08 nM [.sup.35S]GTP.gamma.S. Basal binding
can be determined in the presence of GDP and the absence of test
compounds, and nonspecific binding can be determined by including 10 .mu.M
unlabeled [.sup.35S]GTP.gamma.S. The incubation can be terminated by
filtration under vacuum through glass fiber filters, followed by three
washes with 3 ml ice-cold 50 mM Tris-HCl, pH 7.5. Samples can be allowed
to equilibrate overnight and can be counted in 2 ml Ecoscint A
scintillation fluid for 2 minutes in a liquid scintillation counter.
For [.sup.35S]GTP.gamma.S binding assays, percent stimulation of
[.sup.35S]GTP.gamma.S binding is defined as [(stimulated binding-basal
binding) basal binding].times.100. Percent stimulation is plotted as a
function of compound concentration (log scale), and EC.sub.50 and
E.sub.max values are determined by linear regression analysis. All data is
compared across conditions using ANOVA and non-paired two-tailed Student's
tests. For further details see Huang et al., J. Pharmacol. Exp. Ther.
297:688 (2001); and Zhu et al., J. Pharmacol. Exp. Ther. 282:676 (1997).
Intracranial Self-Stimulation (ICSS)
Intracranial self-stimulation (ICSS) is highly sensitive to the function
of brain reward systems. In this assay, rodents respond to self-administer
rewarding electrical stimulation through electrodes implanted within the
limbic system. Changes in the rewarding efficacy of the stimulation shift
the rate-frequency functions: leftward shifts (reflecting decreases in
ICSS thresholds) imply that the stimulation is more rewarding as a result
of a treatment, whereas rightward shifts (reflecting increases in
thresholds) imply that it is less rewarding. The effects of many types of
treatments on ICSS have been described. Most drugs of abuse decrease the
amount of stimulation required to sustain responding: this is indicated by
leftward shifts in rate-frequency functions and decreased ICSS thresholds.
Conversely, agents that block drug reward (dopamine or kappa-opioid
receptor agonists) increase the amount of stimulation required to sustain
responding: this is indicated by rightward shifts in rate-frequency
functions, and increased ICSS thresholds. Thus ICSS is sensitive to
manipulations that increase or decrease reward.
Considering that mania is typically associated with increases in
reward-driven behavior, the ICSS test may be a reasonable model of mania.
Thus drugs that reduce the rewarding effects of the electrical stimulation
may have some efficacy in the treatment of mania or related states.
Clinical Studies Using the Kappa Agonist Pentazocine
Opiates, which largely target mu opiate receptors, have been given in the
past to patients with bipolar disorder, but specific agonists of KOR have
not been tested in patients with mania. It is not known what sensitivity
patients with mania would have to the mood altering or psychotomimetic
effects of such agents.
No specific kappa agonist is currently approved for human use. However,
the analgesic agent pentazocine is predominantly active at KOR, at which
it is a partial agonist (Zhu et al., 1997). It has lower affinity and
weaker effects at mu opiate receptors and sigma receptors (Bidlack et al.,
2000). In a first trial, we tested whether pentazocine would be well
tolerated and might have mood lowering effects in patients with mania
without causing unwarranted side effects.
Subjects and Design
A trial study was conducted to determine the effect of pentazocine on the
mood of human subjects who have been diagnosed with bipolar disorder and
are acutely manic. Ten subjects (7 male and 3 female) between the ages of
18 and 65 were enrolled in the study. All subjects were admitted to the
hospital with a primary diagnosis of bipolar mania by DSMIV criteria. On
initial evaluation, all subjects had a Young Mania Rating Scale (YMRS)
score of greater than or equal to 14. Subjects with a current history of
substance abuse or a recent history of opiate dependence were excluded.
All subjects were deemed competent to give informed consent by non-study
physicians. After complete description of the study to the subjects,
written informed consent was obtained.
The current study was undertaken in full compliance with federal
requirements and with institutional review board approval. The study was
designed as an open-label cumulative-dosing trial.
The three-day study consisted of pre-treatment, treatment, and
post-treatment days with subjects rated in the morning on all three days
and multiple times on the day of treatment. On the treatment day, an
initial 50 mg of pentazocine was given by mouth. A second dose was given
two hours following the initial dose. Pentazocine was given as Talwin Nx (Sanofi-Synthlabo),
consisting of 50 mg dose pentazocine with 0.5 mg naloxone (naloxone is
added to limit the intra-venous abuse potential of this drug but is not
absorbed when given by oral administration as used here).
Assessment of manic symptoms by YMRS were made daily at the same time in
the morning on all three days of the study. As the YMRS was designed to
reflect the past 48 hours, it is not sensitive to acute symptomatic change
(IsHak et al, 2002) YMRS and DSMIV criteria were used as the basis for
constructing a scale to detect acute changes in manic symptoms (The Mania
Acute Change Scale or MACS). The MACS shows a high correlation with the
YMRS (r=0.81, F=118.0, p<0.01). The MACS scale is available online at
www.mcleanhospital.org. The MACS, which includes items from the YMRS and a
brief assessment of dysphoria/depression was given along with the YMRS in
the morning on all three days of the study. In addition, the MACS was
given hourly for 6 hours starting with the first dose of pentazocine. All
investigator ratings were performed by investigator Beth Murphy, M. D.,
Ph.D. A self-rating scale designed to assess manic symptoms and medication
side effects was completed by subjects whenever the MACS was given. Staff
reports were reviewed, with special note of the duration of sleep and
whether any `pro re nata` (PRN) medications were required. Data were
analyzed using a repeated measures ANOVA (SPSS 14.0).
Administration of pentazocine was well-tolerated. All enrolled subjects
completed the protocol. No subject experienced significant side effects by
clinician ratings or self-report.
All subjects experienced an improvement in manic symptoms (see FIG. 2 (see Original Patent)),
as measured by total score on the MACS, following the administration of
pentazocine (F=3.69, df=5, p=0.01).
No subject experienced exacerbation of psychotic symptoms and most
subjects experienced a mild improvement in psychotic symptoms that
mirrored the improvement in manic symptoms (see FIG. 2, F=3.59, df=5,
p=0.012). There were no differences in PRN medication use over the three
days of the study (pretreatment day=0.8 doses/patient; study day=0.5
doses/patient, p=0.3; post-treatment day=0.3 doses/patient, p=0.6). None
of the subjects complained of dysphoria and there were no consistent
changes in self-ratings of mood (FIG. 3 (see Original Patent)). Clinician
ratings of mood and affect items alone had a trend towards improved mood
but this change was not statistically significant during the five hours
following administration of pentazocine (F=1.4, df=5, p=0.25). Sedation
was low and changes in ratings of sedation were not significant over the
course of the treatment day (FIG. 3; F=1.29, df=5, p=0.29).
Over the three days of the study, YMRS scores improved daily (pretreatment
day YMRS mean=23.6+8.9; treatment day YMRS mean=22.0+6.9; post-treatment
day YMRS mean=12.7+8.4). There was a more substantial improvement between
the treatment and post-treatment days than would be anticipated by the
difference between the pre-treatment and morning of treatment scores (YMRS
on pretreatment vs. treatment day: p=0.4; YMRS on treatment vs.
post-treatment day: p=0.01). Thus, there was no evidence of a rebound in
symptoms after treatment.
Across all subjects, administration of pentazocine was associated with a
transient but substantial and statistically significant reduction in manic
symptoms. This effect did not appear to be due to sedation. No adverse
effects, including psychotomimetic effects, were observed or reported.
Only an acute effect, or two doses, was studied. Nonetheless, these
initial results suggest kappa agonists can be used to lower mood.
Claim 1 of 6 Claims
1. A method of treating mania in a human
subject in need thereof, said method consisting of administering to said
subject an effective amount of a pharmaceutical composition, said
pharmaceutical composition comprising active ingredients and inactive
ingredients, said active ingredients consisting of pentazocine, or a
pharmaceutically acceptable salt thereof, and optionally naloxone.
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