WO2007100335A1

WO2007100335A1 - Methods for the treatment of mood disorders

Info

Publication number: WO2007100335A1
Application number: PCT/US2006/007833
Authority: WO
Inventors: Bruce M. Cohen
Original assignee: The Mclean Hospital Corporation
Priority date: 2006-03-03
Filing date: 2006-03-03
Publication date: 2007-09-07

Abstract

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.

Description

Methods for the Treatment of Mood Disorders

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. CHn. Psychopharmacol. 3:255- 266 (1988)). It has also been long noted that opiates can have euphorogenic 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 m- 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 receptors are also found in areas mediating addiction and reward. In contrast to many opiate-receptor agonists, activation of kappa receptors 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 kappa opiate receptors 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) mediate 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 kappa opiate receptors (see Todtenkopf et al., Psychopharmacology 172:463-470 (2004) and Carlezon et al., Science 282:2272-2275 (1988)). 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. 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 are 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 are 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 subject.

For any of the above methods and kits of the invention the kappa receptor agonist or partial agonist can be dynorphin A 1—17, ethylketocyclazocine, U50,488H, tifluadom, β-funaltrexamine, nalorphine, or pentazocine. Desirably, the kappa receptor agonist or partial agonist is 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, intracerebro ventricular, 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 opioid receptor.

By "kappa receptor agonist" 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 is meant an amount of a compound of the invention which has a therapeutic effect, e.g., which prevents, reduces, or eliminates the mania, mood fluctuations, or reduces CREB activation. 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.

Other features and advantages of the invention will be apparent from the following Detailed Description, the drawings, and the claims.

Brief Description of the Drawings

FIGURE 1 is a graph showing the effect of pentazocine on the mood of human subjects who have been diagnosed with bipolar disorder and are acutely manic. Oral pentazocine was administed as Talwin Nx, which contains 50 mg pentazocine with 0.5mg naloxone.

Detailed Description

Assays

Compounds can be assayed to determine whether they have affinity and efficacy for kappa receptors, and thus are useful in the methods of the invention.

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 [³⁵S]GTPyS 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.

Therapy

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 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 mania.

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 administration.

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.Pv. 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 a 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 level.

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, mood fluctuations, or reduces CREB activation, respectively. Typical dose ranges are from about 0.001 μg/kg to about 2 mg/kg of body weight per day. Desirably, a dose of between 0.001 μg/kg and 1 mg/kg of body weight, or 0.005 μg/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 invention.

Example 1. 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 x g for 10 mm at 4 °C; resuspended in 50 mM Tris-HCl, pH 7.5; homogenized by the use of a Polytron; centrifuged at 48,000 x g for 20 mm at 4 ⁰C; 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 ⁰C until use. Cell membranes are incubated at 25 ⁰C 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 [³H]DAMGO and the kappa- selective ligand [³H]Diprenorphine, and 4 hours of incubation for the delta- selective antagonist [³H]naltrindole. Nonspecific binding is measured by inclusion of 1 μM 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 [³H]Diprenorphine binding, the filters are soaked in 0.1% polyethylenimine for at least 30 minutes before use. IC50 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 = (ICsoVl + 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 binding assay.

Example !. [³⁵S]GTPyS 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 ⁰C in a final volume of 0.5 ml of assay buffer (5OmM Tris-HCl, 3mM MgCl₂, 0.2 mM EGTA, 100 mM NaCl, pH 7.5) containing 3 μM GDP and 0.08 nM [³⁵S]GTPyS. 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 μM unlabeled [³⁵S]GTPyS. 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 [³⁵S]GTPγS binding assays, percent stimulation of [³⁵S]GTPyS binding is defined as [(stimulated binding-basal binding) basal binding] X 100. Percent stimulation is plotted as a function of compound concentration (log scale), and EC₅₀ and E_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, /. Pharmacol. Exp. Ther. 297:688 (2001); and Zhu et al., J. Pharmacol Exp. Ther. 282:676 (1997).

Example 3. 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. Example 4. Clinical Studies Using the Kappa Agonist Pentazocine

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. Oral pentazocine was administed as Talwin Nx, which contains 50 mg pentazocine with 0.5mg naloxone. Naloxone is added to limit the IV abuse potential in outpatients.

On the day of the study, 50mg of pentazocine was given orally. Two hours after the administration of the initial dose, an additional 50mg of pentazocine was given. Patients were monitored prior to pentazocine treatment, during treatment, and post-treatment. Structured MINI for bipolar disorder, mania, and depression, Young Mania Rating Scale, kappa mania scale, and the kappa mania self report tests were conducted.

Possibilities for mania scores on the Young Mania Rating scale range from 0-60, with most inpatient scores in the range of 20-50. A change in score of 5 points would be clinically relevant. Possibilities for mania scores on the Kappa Rating scale range from 0-56. A change in score of 10 points would be clinically relevant.

During treatment, the Kappa Ratings Scale was measured at hours 0, 1, 2, 3, 4, and 5. The changes observed in the Kappa score following pentazocine treatment at hours 0 and 2 (see Figure 1) demonstrate that pentazocine treatment reduces mania.

Other Embodiments All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims. What is claimed is:

Claims

1. A method of treating mania in a human subject in need thereof, said method comprising administering to said mammal an effective amount of a kappa receptor agonist or partial agonist.

2. The method of claim 1, wherein said subject is diagnosed with bipolar disorder, acute mania, or chronic mania.

3. The method of claim 1, wherein said mania occurs in a single episode or is recurring.

4. A method for treating bipolar disorder in a human subject in need thereof, said method comprising administering to said subject an effective amount of a kappa receptor agonist or partial agonist.

5. A method for stabilizing the mood of a human subject diagnosed with a mood disorder, said method comprising administering to said mammal an effective amount of a selective kappa receptor agonist or partial agonist.

6. The method of any of claims 1-5, wherein said kappa receptor agonist or partial agonist is dynorphin A 1-17, ethylketocyclazocine, U50,488H, tifluadom, β-funaltrexamine, nalorphine, or pentazocine.

7. The method of claim 6, wherein said kappa receptor agonist or partial agonist is pentazocine.

8. A kit comprising (i) a compound having kappa receptor agonist or partial agonist activity, and (ii) instructions for the administration of said compound for the treatment of mania.

9. A kit comprising (i) a compound having kappa receptor agonist or partial agonist activity, and (ii) instructions for the administration of said compound for the treatment of bipolar disorder.

10. A kit comprising (i) a compound having kappa receptor agonist or partial agonist activity, and (ii) instructions for the administration of said compound for stabilizing the mood of a subject.

11. The kit of any of claims 8-10, wherein said kappa receptor agonist or partial agonist is dynorphin A 1—17, ethylketocyclazocine, U50,488H, tifluadom, β-funaltrexamine, nalorphine, or pentazocine.

12. The kit of claim 11 , wherein said kappa receptor agonist or partial agonist is pentazocine.