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US0078.93053B2

(12) United States Patent (10) Patent No.: US 7,893,053 B2 Seed et al. (45) Date of Patent: Feb. 22, 2011

(54) TREATING PSYCHOLOGICAL CONDITIONS WO WO 2006/127418 11, 2006 USING MUSCARINIC RECEPTORM ANTAGONSTS (75) Inventors: Brian Seed, Boston, MA (US); Jordan OTHER PUBLICATIONS Mechanic, Sunnyvale, CA (US) Chau et al. (Nucleus accumbens muscarinic receptors in the control of behavioral depression : -like effects of local M1 (73) Assignee: Theracos, Inc., Sunnyvale, CA (US) antagonist in the porSolt Swim test Neuroscience vol. 104, No. 3, pp. 791-798, 2001).* (*) Notice: Subject to any disclaimer, the term of this Lind et al. (Muscarinic receptor antagonists inhibit patent is extended or adjusted under 35 chick Scleral chondrocytes Investigative Ophthalmology & Visual U.S.C. 154(b) by 726 days. Science, vol.39, 2217-2231.* Chau D., et al., “Nucleus Accumbens Muscarinic Receptors in the (21) Appl. No.: 11/763,145 Control of Behavioral Depression: Antidepressant-like Effects of Local M1 Antagonists in the Porsolt Swin Test.” Neuroscience, vol. (22) Filed: Jun. 14, 2007 104, No. 3, Jun. 14, 2001, pp. 791-798. Bechtel, W.D., et al., “Biochemical pharmacology of . (65) Prior Publication Data Similarities with in antimuscarinic effects only.” Arzneimittelforschung, vol. 36(5), pp. 793-796 (May 1986). US 2007/O293480 A1 Dec. 20, 2007 Chau, D.T. et al., “Nucleus accumbens muscarinic receptors in the control of behavioral depression: antidepressant-like effects of local Related U.S. Application Data Mantagonist in the Porsolt Swim test.” Neuroscience, vol. 104(3), (60) Provisional application No. 60/805,066, filed on Jun. pp. 791-798 (Jun. 2001). 16, 2006, provisional application No. 60/829,225, Hammer, R., et al., “The pharmacokinetic profile of pirenzepine.” filed on Oct. 12, 2006. Scand. J. Gastroenterol. Suppl., vol. 57, pp. 1-6 (1979). Ichikawa, J., et al., “ modulation of basal and amphet amine-induced release in rat medial prefrontal cortex and (51) Int. Cl. nucleus accumbens.” Brain Research, vol. 958, pp. 176-184 (2002). AOIN 43/62 (2006.01) Miyakawa, T., et al., “Hyperactivity and intact hippocampus-depen A63/55 (2006.01) dent learning in mice lacking the M1 muscarinic acetylcholine recep A6 IK 3/4965 (2006.01) tor.” The Journal of Neuroscience, vol. 21 (14), pp. 5239-5250 (Jul. AOIN 43/54 (2006.01) 2001). AOIN 47/28 (2006.01) Rogóz, et al., “Central Action of Pirenzepine.” Pol. J. Pharmacol. (52) U.S. Cl...... 514/220; 514/255.01: 514/256; Pharm., vol. 33, pp. 615-626 (1981). 514758O Trummlitz, G., et al., "Conformational analysis of the antiulcer drug (58) Field of Classification Search ...... 514/220 pirenzepine. X-ray investigations, molecular mechanics and quan See application file for complete search history. tum mechanical calculations and comparisons with structurally or pharmacologically related compounds.” Arzneimittelforschung, vol. (56) References Cited 34(8), pp. 849-859 (1984). Chau et al. (Nucleus accumbens muscarinic receptors in the control U.S. PATENT DOCUMENTS of behavioral depression : Antidepressant-like effects of local M1 3,953,430 A 4, 1976 Safir antagonist in the porSolt Swim test Neuroscience vol. 104, No. 3, pp. 4,536,518 A 8, 1985 Welch, Jr. et al. 791-798, 2001). 4,839,104 A 6/1989 Quallich et al. (Continued) 4,940,731 A 7, 1990 Bick Primary Examiner Sreeni Padmanabhan 4,962,128 A 10/1990 Doogan et al. Assistant Examiner—Layla Soroush 5,114,976 A 5, 1992 Norden (74) Attorney, Agent, or Firm Kilpatrick Townsend & 5,130,338 A 7/1992 Bacopoulos Stockton 5,248,699 A 9/1993 Sysko et al. 5,442,116 A 8, 1995 Welch et al. (57) ABSTRACT 5,597,826 A 1/1997 Howard et al. 5,744,501 A 4, 1998 Norden 5,789,449 A 8, 1998 Norden Provided are methods of treating psychological and 6,034,274. A * 3/2000 Vukics et al...... 564,308 conditions by administration of a preferential muscarinic ace 6,517,866 B1 2/2003 Am Ende et al. tylcholine receptor Mantagonist, optionally with at least one 6,727,283 B2 4/2004 Harper et al. antidepressant other than a selective muscarinic acetylcho 7,067,555 B2 6/2006 Harper et al. line receptor Mantagonist. The invention also provides for 2004/0082653 A1 4/2004 Nonaka et al. pharmaceutical compositions and kits for administration of at 2005/0227998 A1 10/2005 Voelker least one selective muscarinic M antagonist in combination with at least one antidepressant other than a selective muscarinic acetylcholine receptor M antagonist. FOREIGN PATENT DOCUMENTS WO WO 2006/113485 10, 2006 10 Claims, 6 Drawing Sheets US 7,893,053 B2 Page 2

OTHER PUBLICATIONS Cryan et al., “The Tail Suspension Test as a Model for Assessing Antidepressant Activity: Review of Pharmacological and Genetic Lind et al. (Muscarinic acetylcholine receptor antagonists inhibit Studies in Mice.” Neurosciences and Biobehavioral Reviews, 29 chick Scleral chondrocytes Investigative Ophthalmology & Visual (2005) 571-625. Science, vol.39, 2217-2231, Nov. 1998. Steru et al., “The Tail Suspension Test: A New Method for Screening Crowley et al., “Automated Tests for Measuring the Effects of Anti Antidepressants in Mice.” Psychopharmacology (1985)85: 367-370. depressants in Mice.” Pharmacology, Biochemistry and Behavior, 78 (2004) 269-274. * cited by examiner

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f O g 92 O O O O O DeSuW) eqoulu I Aueds eul US 7,893,053 B2 1. 2 TREATING PSYCHOLOGICAL CONDITIONS pp. 615-26). The lack of such effects can be explained by the USING MUSCARINIC RECEPTORM observation that pirenzepine does not exhibit significant pen ANTAGONSTS etration of the blood-brain barrier in various species, includ ingrodents and humans (see, Hammer, R., Koss, F.W., Scand. CROSS-REFERENCE TO RELATED 5 J. GastroenteroL, Suppl., 1979, Vol. 14, no. 57, pp. 1-6: APPLICATIONS Bymaster, F. P. et al., J. Pharmacol. Exp. Ther:, 1993, Vol. 267, no. 1, pp. 16-24). It is for that reason that the above This application claims the benefit of U.S. Provisional mentioned study of the effect of pirenzepine in the Porsolt Application No. 60/805,066, filed Jun. 16, 2006 and U.S. swim test utilized direct injection of the drug into the brain of Provisional Application No. 60/829,225, filed Oct. 12, 2006, 10 test animals. the entire disclosures of both of which are hereby incorpo There exists a need for new and effective for rated herein by reference. the treatment of psychological conditions, including depres Sion. The present invention addresses this and other needs. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED 15 BRIEF SUMMARY OF THE INVENTION RESEARCH AND DEVELOPMENT The present invention provides methods for treating vari Not Applicable ous psychological disorders, including depression, by sys temically administering a therapeutically effective amount of FIELD OF THE INVENTION one or more muscarinic M1 receptor (MR-selective) antago nists. In practicing the present methods, the one or more The present invention relates to the treatment of psycho MR-selective antagonists can be administered without other logical disorders, including depression, by administration of pharmacological agents or in combination with other phar a selective M muscarinic receptor (MIR) antagonist, alone or macological agents, for example, one or more antidepressants in combination with an antidepressant. 25 other than a MR-selective antagonist. Accordingly, in a first aspect, the present invention pro BACKGROUND OF THE INVENTION vides methods for treating one or more psychological condi tions or disorders by Systemically administering to an indi The neurotransmitter acetylcholine (ACh) interacts with vidual in need thereof a therapeutically effective amount of two types of receptors in effector cell membranes: nicotinic 30 one or more selective MR-selective antagonists, whereby the receptors (nAChR), which are ligand-gated ion channels, and one or more psychological conditions are treated. muscarinic receptors (mAChR), which are G protein-coupled In a related aspect, the invention provides methods for receptors. In mammals five Subtypes of mAChR, designated treating one or more psychological conditions or disorders by M to Ms., have been identified. The M muscarinic receptor administering to an individual in need thereof a therapeuti (MR) is found in both the central and peripheral nervous 35 systems, particularly the cerebral cortex and sympathetic cally effective amount of a combination of one or more MR ganglia. The muscarinic effects mediated by MR have been selective antagonists and one or more antidepressants other studied largely by use of MR-selective antagonists and, more than a MR-selective antagonist, whereby the one or more recently, by the development of MR-null mice. psychological conditions are treated. Although no currently known mAChRantagonists display 40 In one embodiment, the psychological disorder is an affec absolute selectivity for a single muscarinic receptor Subtype, tive disorder. In one embodiment, the psychological condi the drugs pirenzepine and exhibit high relative tion is depression. In one embodiment, the psychological condition is selected from the group consisting of depression, affinity for MR and are therefore often considered MR , , , obsessive selective. Pirenzepine is used to treat peptic ulcer in compulsive disorder, post-traumatic stress disorder, body Europe, Japan and Canada. TelenZepine has been tested in 45 clinical trials for the same indication. At therapeutic doses, dysmorphic disorder, premenstrual dysphoric disorder, and they moderately reduce and pepsin secretion Substance abuse and/or dependence. without inhibiting Smooth muscle activity as do non-selective In another aspect, the invention provides pharmaceutical mAChRantagonists. compositions comprising a mixture of therapeutically effec There are several lines of evidence suggesting that the MR 50 tive amounts of one or more MR-selective antagonists and Subtype may be involved in certain aspects of depressive one or more antidepressants other than a MR-selective disorders and anxiety. Direct injection of pirenzepine into the antagonist. nucleus accumbens in the forebrain of rats resulted in In another aspect, the invention provides kits comprising a increased Swimming time in the Porsolt Swim test (see, Chau, mixture of therapeutically effective amounts of one or more D. T., et al., Neuroscience, 2001, vol. 104, no. 3, pp. 791-8), a 55 MR-selective antagonists and one or more antidepressants common measure of antidepressant activity. MR-null mice other than a MR-selective antagonist. also displayed increased Swimming time in the Porsolt Swim With regard to the embodiments for carrying out the meth test, as well as increased social contacts in a social interaction ods, and for the pharmaceutical compositions and kits, in one test (see, Miyakawa, T., et al., J. Neurosci., 2001, Vol. 21, no. embodiment, the one or more MR-selective antagonists is 14, pp. 5239-50). 60 selected from the group consisting of pirenzepine, telen While pirenzepine and telenzepine are structurally similar Zepine, and combinations thereof. In one embodiment, the to tricyclic antidepressants such as , they are not MR-selective antagonist is telenzepine (racemic or an opti known to have psychotropic effects when taken orally for the cal isomer). In one embodiment, the MR-selective antago treatment of . In addition, in earlier stud nist is pirenzepine. ies of mice and rats, pirenzepine administered systemically 65 In one embodiment, the one or more MR-selective failed to elicit any behavioral effects (see, Rogoz, Z. Skuza, antagonists are administered without a second pharmacologi G., Sowinska, H., Pol. J. Pharmacol. Pharm., 1981, Vol. 31, cal agent. US 7,893,053 B2 3 4 In one embodiment, the one or more MR-selective In one embodiment, the one or more MR-selective antagonists is administered in combination with or combined antagonists is telenzepine (racemic or an optical isomer) and with one or more antidepressants other than a MR-selective the one or more antidepressants other than a MR-selective antagonist. In one embodiment, the antidepressant is selected antagonist is . from the group consisting of a selective In a related aspect, the invention provides methods for inhibitor (SSRI) and a selective serotonin- preparing or use of a medicament for treating one or more (SNRI). psychological conditions, the medicament containing athera In one embodiment, the antidepressant is a SSRI. In one peutically effective amount of one or more MR-selective embodiment, the SSRI is selected from the group consisting antagonists. The medicament can optionally also contain one of , , , , paroX 10 or more antidepressants other than a MR-selective antago etine and . In one embodiment, the SSRI is selected nist. The embodiments for the medicament are as described from the group consisting of citalopram, Sertraline, paroxet herein. ine, and fluoxetine. In some embodiments, the methods and compositions of In one embodiment, the antidepressant is a SNRI. In one the invention comprise the combinations of pharmacological embodiment, the SNRI is selected from the group consisting 15 agents set forth herein. In some embodiments, the methods of , , , dulloxetine, des and compositions of the invention consist essentially of the venlafaxine and . In one embodiment, the SNRI is combinations of pharmacological agents set forth herein. Venlafaxine. Efficacious results can be achieved without timed admin Definitions istration of the one or more MR-selective antagonists. Co administered active agents, including antidepressants, also The term “psychological disorder or “psychological con provide efficacious results without timed administration. dition' interchangeably refer to a disorder of thought or emo In one embodiment, the one or more MR-selective tion or a disorder of the brain that results in a disruption in a antagonists is telenzepine (racemic or an optical isomer) and person’s thinking, feeling, moods, and ability to relate to the one or more antidepressants other than a MR-selective 25 others. A psychological disorder or condition can manifest as antagonist is fluoxetine (racemic or an optical isomer). inappropriate or unprovoked expressions of anger, sadness, In one embodiment, the one or more MR-selective fear, anxiety, or other sociopathic behaviors, for example. antagonists is telenzepine (racemic or an optical isomer) and Exemplified categories of psychological disorders include, the one or more antidepressants other than a MR-selective without limitation, affective disorders, anxiety disorders, antagonist is fluvoxamine. 30 cognitive disorders, control disorders, Substance In one embodiment, the one or more MR-selective abuse/dependence disorders, attention deficit/hyperactivity antagonists is telenzepine (racemic or an optical isomer) and disorders, eating disorders, movement disorders and sexual the one or more antidepressants other than a MR-selective dysfunctions. Exemplified psychological conditions treatable antagonist is Sertraline or its S-, Zoloft. by the present methods and compositions include, without 35 limitation, depression, anxiety, Social anxiety disorder, ago In one embodiment, the one or more MR-selective raphobia, obsessive-compulsive disorder, post-traumatic antagonists is telenzepine (racemic or an optical isomer) and stress disorder, , premenstrual dys the one or more antidepressants other than a MR-selective phoric disorder and Substance abuse? dependence. Psycho antagonist is citalopram (or escitalopram). logical disorders are described, for example, in Halgin and In one embodiment, the one or more MR-selective 40 Whitbourne, Abnormal Psychology: Clinical Perspectives antagonists is telenzepine (racemic or an optical isomer) and On Psychological Disorders, 4th Edition, 2005, McGraw the one or more antidepressants other than a MR-selective Hill College; Barlow and Antony, Handbook of Assessment antagonist is . and Treatment Planning for Psychological Disorders, 2002, In one embodiment, the one or more MR-selective antagonists is telenzepine (racemic or an optical isomer) and Guilford Press; Claridge and Davis, Personality and Psycho 45 logical Disorders, 2003, Oxford Univ Pr; and Clinical Hand the one or more antidepressants other than a MR-selective book of psychological Disorders. A Step-by-Step Treatment antagonist is Venlafaxine (racemic or an optical isomer). Manual, Barlow, Ed., 2001, Guilford Press. Diagnostic crite In one embodiment, the one or more MR-selective ria for recognized psychological disorders can be made with antagonists is telenzepine (racemic or an optical isomer) and reference to Diagnostic and Statistical Manual of Mental the one or more antidepressants other than a MR-selective 50 Disorders (DSM IV. 2000, American Psychiatric Associa antagonist is . tion). In one embodiment, the one or more MR-selective The term “affective disorder” refers to any disorder of antagonists is telenzepine (racemic or an optical isomer) and mood. Affective disorders include depression, mania, bipolar the one or more antidepressants other than a MR-selective disorder, seasonal affective disorder, anxiety, panic. See, for antagonist is . 55 example, Paykel, Handbook of Affective Disorders, 1992, In one embodiment, the one or more MR-selective Longman Group Ltd. antagonists is telenzepine (racemic or an optical isomer) and The term “depression” refers to a clinical syndrome con the one or more antidepressants other than a MR-selective sistent with its accepted meaning in the art (see, for example, antagonist is sibutramine. Diagnostic and Statistical Manual of Mental Disorders, In one embodiment, the one or more MR-selective 60 Fourth Edition, Text Revision DSM-IV-TR): American Psy antagonists is telenzepine (racemic or an optical isomer) and chiatric Association, 2000; American Psychiatric Publishing, the one or more antidepressants other than a MR-selective Inc., Arlington, Va.). Symptoms of depression include, but are antagonist is milnacipran. not limited to, persistent sadness, feelings of pessimism, In one embodiment, the one or more MR-selective despair, feelings of helplessness, feelings of worthlessness, antagonists is telenzepine (racemic or an optical isomer) and 65 changes in moods, agitation, irritability, restlessness, loss of the one or more antidepressants other than a MR-selective interest or pleasure in activities once enjoyed, thoughts of antagonist is mirtazapine. death or , inability to concentrate or make decisions, US 7,893,053 B2 5 6 mental slowness, , decreased energy, or muscarinic acetylcholine that exhibits oversleeping, loss of appetite or overeating, weight loss or preferential interaction with the muscarinic receptor M sub weight gain, persistent or digestive disorders, type in comparison to the muscarinic receptor subtypes M. chronic pain, and abnormal hormonal circadian rhythms. and M. Exemplified MR-selective antagonists include, but The term “' is used in accordance with its commonly understood meaning by those of skill in are not limited to, pirenzepine and telenzepine. Preferential the art. For example, a clinical diagnosis of “substance depen binding need not be complete. For example, despite compa dence” according to the International Classification of Dis rable affinities for M and M receptor subtypes, pirenzepine eases requires that three or more of the following must have is classified as an MR-selective antagonist. been experienced or exhibited by the individual at some time 10 Preferential binding of a MR-selective antagonist can be during the previous year: (1) difficulties in controlling Sub measured in a competitive displacement assay. A M R-selec stance-taking behavior in terms of its onset, termination, or tive antagonist will preferentially displace a known MR levels of use; (2) a strong desire or sense of compulsion to take selective ligand (e.g. pirenzepine and/or telenzepine) in com the Substance; (3) progressive neglect of alternative pleasures parison to known M. (e.g. tripitramine, , or interests because of psychoactive substance use, increased 15 amount of time necessary to obtain or take the Substance or to ) and M. (e.g. , hexahydrosilad recover from its effects; (4) persisting with Substance use iphenidol) selective ligands. Alternatively, a MR-selective despite clear evidence of overtly harmful consequences, antagonist will preferentially displace a nonselective musca depressive mood states consequent to heavy use, or drug rinic ligand (e.g., quinuclidinyl benzilate (QNB), N-meth related impairment of cognitive functioning; (5) evidence of ylscopolamine (NMS)) from an M receptor subtype in com tolerance. Such that increased doses of the psychoactive Sub parison to displacing the non-selective muscarinic ligand stance are required in order to achieve effects originally pro from binding to the M and M receptor subtypes. The relative duced by lower doses; (6) a physiological withdrawal state potencies for displacement of radiolabeled competitors can when Substance use has ceased or been reduced, as evidence be expressed in terms of the concentration at which 50% of by: the characteristic withdrawal syndrome for the substance: 25 the competitor is displaced (ICs), or in terms of an equilib or use of the same (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms. Fur rium dissociation constant (K). The ICso value and/or the ther information regarding Substance abuse can be found, for equilibrium dissociation constant can be calculated using example, on the website for the National Institute on Drug available software by entering the values of detected labeled Abuse (NIDA) at nida.nih.gov. 30 ligand in the presence of titrated amounts of unlabeled test As used herein, “administering means oral ("po') admin compound (e.g., LIGAND (Munson, P. J., and Rodbard, D., istration, administration as a suppository, topical contact, Anal. Biochem. (1980) 107:220-39 or DATAPLOT, National intravenous (“iv'), intraperitoneal (“ip'), intramuscular Technical Information Services). AMR-selective antagonist (“im'), intralesional, intranasal or subcutaneous (“sc' will have an ICso value or a K value for binding to an M. administration, or the implantation of a slow-release device 35 receptor subtype that is at least about 3-fold less, preferably at e.g., a mini-osmotic pump, to a Subject. Administration is by any route including parenteral and transmucosal (e.g., oral, least about 10-fold less, and more preferably at least about nasal, vaginal, rectal, or transdermal). Parenteral administra 30-fold less than its ICs value or K value for binding to M, tion includes, e.g., intravenous, intramuscular, intra-arteriole, and M receptor Subtypes. Applicable radioligand binding intradermal, Subcutaneous, intraperitoneal, intraventricular, 40 assays, using radiolabeled NMS or QNB, are disclosed in and intracranial. Other modes of delivery include, but are not Buckley, et al., Molecular Pharmacolog (1989) 35:469-76 limited to, the use of liposomal formulations, intravenous and Bolden, etal, J Pharmacol Exp. Ther. (1992) 260:576-80. infusion, transdermal patches, etc. As used herein, the phrase “consisting essentially of refers The terms “systemic administration' and “systemically to the genera or species of active pharmaceutical agents administered refer to a method of administering a compound 45 or composition to a mammal so that the compound or com included in a method or composition, as well as any excipi position is delivered to sites in the body, including the tar ents inactive for the intended purpose of the methods or geted site of pharmaceutical action, via the circulatory sys compositions. In some embodiments, the phrase “consisting tem. Systemic administration includes, but is not limited to, essentially of expressly excludes the inclusion of one or oral, intranasal, rectal and parenteral (i.e., other than through 50 more additional active agents other than a MR-selective the alimentary tract, Such as intramuscular, intravenous, intra antagonist and an antidepressant. In some embodiments, arterial, transdermal and Subcutaneous) administration, with additional active agents that can be excluded include one or the proviso that, as used herein, Systemic administration does more of a inhibitor, a prolactin stimulator, a 5-HT not include direct administration to the brain region by means receptor antagonist, a 5-HT receptoragonist, a NK-1 receptor other than via the circulatory system, Such as intrathecal 55 antagonist and/or a dipeptidylpeptidase IV inhibitor. injection and intracranial administration. The term “co-administer” refers to the simultaneous pres The terms “controlled release.” “sustained release.” ence of two active agents in the blood of an individual. Active “extended release, and “timed release' are intended to refer agents that are co-administered can be concurrently or interchangeably to any drug-containing formulation in which sequentially delivered. 60 release of the drug is not immediate, i.e., with a “controlled As used herein, the terms “treating and “treatment” refer release' formulation, oral administration does not result in to delaying the onset of retarding or reversing the progress of immediate release of the drug into an absorption pool. The or alleviating or preventing either the disease or condition to terms are used interchangeably with “nonimmediate release' which the term applies, or one or more symptoms of Such as defined in Remington. The Science and Practice of Phar disease or condition. 65 macy, 21 Ed., Lippencott Williams & Wilkins (2006). As As used herein, the terms 'selective muscarinic receptor discussed therein, immediate and nonimmediate release can Mantagonist' and “MR-selective antagonist” refer to a be defined kinetically by reference to the following equation: US 7,893,053 B2 8 FIG. 5 illustrates the effect of combined administration of telenzepine (TZP) and venlafaxine (VEN) on immobility Dosage k Absorption ka Target ke times of CD-I mice subjected to the tail suspension test. Male Form drug Pool absorption Area elimination CD-1 mice (n=10 per group) were administered intraperito release neally as free base telenzepine alone (5.0 mg/kg), Venlafaxine alone (10 mg/kg), or co-administered telenzepine (5.0 mg/kg) The “absorption pool' represents a solution of the drug and Venlafaxine (10 mg/kg) as described in the Examples administered at a particular absorption site, and k, k, and k. below. Control mice (VEH) were administered 10% DMSO. are first-order rate constants for (1) release of the drug from * indicates p<0.05 vs. VEH. ** indicates p<0.01 vs. VEH. the formulation, (2) absorption, and (3) elimination, respec 10 “aa’ indicates p<0.01 vs. VEN. “bindicates p<0.05 vs. TZP. tively. For immediate release dosage forms, the rate constant for drug release k, is far greater than the absorption rate FIG. 6 illustrates the effect of combined administration of constant k. For controlled release formulations, the opposite telenzepine (TZP) and fluoxetine (FLX) on immobility times is true, i.e., k,

TABLE 1.

Vehicle Treatment Dose Immobility Immobility Reduction in Compound (mg/kg) Time (sec) Time (sec) Immobility p Values

Telenzepine 5 (ip) 15 - 16 80 - 14 30% l.S. 5 (ip) 14 + 19 90- 18 21% l.S. 5 (ip) 25 14 159 23 -27% l.S. 10 (ip) 97 - 20 64 15 34% l.S. 25 (ip) 25 14 84 O7 33% : 50 (ip) 25 14 6111 51% ::::::::: 60 (po) 30 21 71 - 15 45% : 80 (po) 30 21 82 - 18 37% : 100 (po) 30 21 59 10 55% :::::: Pirenzepine 5 (ipy 23 - 20 137 - 15 -1.1% l.S. 25 (ipy 23 - 20 90 - 17 27% l.S. 50 (ipy 23 - 20 76 - 12 38% : Fluoxetine 4 (ip) 97 - 20 97 - 11 O% 4 (ip)s 46 - 18 81 - 16 45% 20 (ip) 46 - 18 8216 45% :::::: 40 (ip) 46 - 18 53 - 14 64% ::::::::: Sertraline 1 (ip) 1516 87 - 14 24% 5 (ip) 21 - 17 63 - 08 48% 20 (ip)" 21 - 17 SO 16 59% :::::: 40 (ip)" 21 - 17 44 - 15 64% ::::::::: Venlafaxine 3 (ip) 1215 103 - 21 8% l.S. 10 (ip) 1215 116 20 -4% l.S. 10 (ip) 1419 103 - 15 10% l.S. 30 (ip) 1215 31 O9 729% ::::::::: Telenzepine + 10 + 4 (ip) 97 - 20 45-09 54% :::::: Fluoxetine Telenzepine + 5 + 1 (ip) 1516 66 12 43% ::::::::: Sertraline Telenzepine + 5 + 10° (ip) 1419 29 O9 75% :::::: , aa, b Venlafaxine

Note on Effects: co-administered with 5 mg/kg telenzepine. It is estimated that As Summarized in Table 1, Systemic administration of the effective fluoxetine dose can be lowered approximately pirenzepine alone at 50 mg/kg ip (FIG. 1) or telenzepine alone 35 7-fold (to 4 mg/kg) by co-administering 10 mg/kg. TZP. at 25 mg/kg ip (FIG. 2) or 60 mg/kg po (FIG. 3) produces It is understood that the examples and embodiments significant reduction in immobility. described herein are for illustrative purposes only and that various modifications or changes in light thereofwill be Sug When telenzepine is co-administered with an antidepres gested to persons skilled in the art and are to be included sant, all three combinations tested display the principle that 40 Subactive doses of each compound can be combined to pro within the spirit and purview of this application and scope of duce significant effects that generally appear synergistic. The the appended claims. All publications, patents, and patent telenzepine--Venlafaxine combination demonstrated the applications cited herein are hereby incorporated by refer greatest efficacy of the tested combinations. Co-administra ence in their entirety for all purposes. tion of telenzepine and Venlafaxine produces a significant 45 (p<0.01) reduction of 75%, well beyond the 31% reduction What is claimed is: that would be expected from mere additivity (FIG. 5). Like 1. A method for enhancing the antidepressant effect of an wise, co-administration of 10 mg/kg telenzepine-4 mg/kg antidepressant selected from the group consisting of a selec fluoxetine results in a significant (p<0.01) reduction in immo tive serotonin reuptake inhibitor (SSRI) or a serotonin-nore bility of 54%, an effect greater than expected from the con 50 pinephrine reuptake inhibitor (SNRI), the method comprising tributions of the individual compounds (FIG. 6). Co-admin systemically co-administering to an individual in need istration of telenzepine and Sertraline produces a significant thereof telenzepine and a SSRI or a SNRI selected from the 43% reduction in immobility (FIG. 4). group consisting of Venlafaxine, Sertraline and fluoxetine in a therapeutically effective amount to treat depression, thereby The combinations of selective MR-antagonists and anti enhancing the antidepressant effect of the SSRI or the SNRI. depressants demonstrate that the “effective dose” of the anti 55 depressant compound can be lowered dramatically by co 2. The method of claim 1, wherein the SSRI is fluoxetine. administering an MR-antagonists (e.g. telenzepine). The 3. The method of claim 1, wherein the SSRI is sertraline. venlafaxine dose can be lowered 3 fold (to 10 mg/kg) and still 4. The method of claim 1, wherein the SNRI is venlafaxine. retain efficacy by co-administering 5 mg/kg telenzepine. 5. The method of claim 1, wherein the telenzepine is Compare the 72% reduction in immobility when 30 mg/kg 60 administered in a Sustained-release formulation. venlafaxine is administered alone to the 75% reduction in 6. An improved method for treating depression with an immobility when 10 mg/kg Venlafaxine is co-administered antidepressant selected from the group consisting of a SSRI with 5 mg/kg telenzepine. Similarly, the sertraline dose can be or an SNRI, the improvement comprising systemically co lowered 5-fold (to 1 mg/kg) and still retain efficacy by co administering to an individual in need thereof telenzepine and administering 5 mg/kg. TZP. Compare the 48% reduction in 65 a SSRI or a SNRI selected from the group consisting of immobility when 5 mg/kg Sertraline is administered alone to Venlafaxine, Sertraline and fluoxetine in a therapeutically the 43% reduction in immobility when 1 mg/kg sertraline is effective amount to treat depression. US 7,893,053 B2 25 26 7. The method of claim 6, wherein the SSRI is fluoxetine. 10. The method of claim 6, wherein the telenzepine is 8. The method of claim 6, wherein the SSRI is sertraline. administered in a Sustained-release formulation. 9. The method of claim 6, wherein the SNRI is venlafaxine. k . . . . UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 7,893,053 B2 Page 1 of 1 APPLICATIONNO. : 1 1/763145 DATED : February 22, 2011 INVENTOR(S) : Seed et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Title page, item (56) (References Cited), Second Column, first entry in OTHER PUBLICATIONS subsection: delete this first cite to “Chau et al. (Nucleus accumbens muscarinic receptors in the control of behavioral depression : Antidepressant-like effects of local M1 antagonist in the porsolt swim test Neuroscience vol. 104, No. 3, pp. 791-798, 2001). Title page, item (56) (References Cited), Second Column, in the third cite entry in OTHER PUBLICATIONS Subsection, line 10 within the Subsection, in the “Chau D., et al. cite: delete “Swin' and insert --Swim--.

Title page, item (56) (References Cited), Second Column, in the third cite entry in OTHER PUBLICATIONS Subsection, line 11 within the Subsection, at the end of the “Chau D., et al. Cite, insert ----. Title page, item (56) (References Cited), Second Column, final entry in OTHER PUBLICATIONS Subsection: delete this final cite to “Chau et al. (Nucleus accumbens muscarininc receptors in the control of behavioral depression : Antidepressant-like effects of local M1 antagonist in the porsolt swim test Neuroscience vol. 104, No. 3, pp. 791-798, 2001).

Signed and Sealed this Twenty-fifth Day of October, 2011

David J. Kappos Director of the United States Patent and Trademark Office