(12) Patent Application Publication (10) Pub. No.: US 2009/0018115 A1 Gaddle Et Al

US 2009001 8115A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0018115 A1 Gaddle et al. (43) Pub. Date: Jan. 15, 2009

(54) COMPOSITIONS OF AN ANTICONVULSANT on Oct. 5, 2004, provisional application No. 60/535, AND AN ANTIPSYCHOTC DRUG AND 799, filed on Jan. 13, 2004, provisional application No. METHODS OF USING THE SAME FOR 60/535,800, filed on Jan. 13, 2004. AFFECTING WEIGHT LOSS Publication Classification (75) Inventors: Kishore M. Gadde, Durham, NC (US); K. Ranga Krishnan, Chapel (51) Int. Cl. Hill, NC (US) A63L/35 (2006.01) A6II 3L/22 (2006.01) Correspondence Address: A6II 3/42 (2006.01) KNOBBE MARTENS OLSON & BEAR LLP A6II 3/55 (2006.01) 2040 MAINSTREET, FOURTEENTH FLOOR A63L/435 (2006.01) IRVINE, CA 92.614 (US) (52) U.S. Cl...... 514/214.02: 514/546; 514/557: (73) Assignee: Orexigen Therapeutics, Inc., San 514/574: 514/455; 514/397: 514/284 Diego, CA (US) (57) ABSTRACT (21) Appl. No.: 12/239,574 Disclosed are compositions for affecting weight loss com (22) Filed: Sep. 26, 2008 prising a first compound and a second compound, where the first compound is a psychotherapeutic agent and the second Related U.S. Application Data compound is a anticonvulsant. Also disclosed are methods of affecting weight loss, increasing energy expenditure, increas (63) Continuation of application No. 11/034.316, filed on ing Satiety in an individual, or suppressing the appetite of an Jan. 11, 2005, now Pat. No. 7,429,580. individual, comprising identifying an individual in need (60) Provisional application No. 60/567,896, filed on May thereof and treating that individual with a psychotherapeutic 3, 2004, provisional application No. 60/616,393, filed agent and an anticonvulsant. US 2009/00181 15 A1 Jan. 15, 2009

COMPOSITIONS OF AN ANTICONVULSANT combination of fenfluramine and phentermine. Unfortu AND AN ANTIPSYCHOTC DRUG AND nately, it was discovered that fenfluramine caused heart-valve METHODS OF USING THE SAME FOR complications, which in some cases resulted in the death of AFFECTING WEIGHT LOSS the user. Fenfluramine has since been withdrawn from the market. There has been some limited success with other com RELATED APPLICATIONS bination therapy approaches, particularly in the field of psy chological eating disorders. One Such example is Devlin, et 0001. The present application is a continuation of, and al., Int J. Eating Disord. 28:325-332, 2000, in which a com claims priority to, U.S. patent application Ser. No. 11/034, bination of phentermine and fluoxetine showed some efficacy 316, filed on Jan. 11, 2005, now U.S. Pat. No. 7,429,580, in the treatment of binge eating disorders. Of course, this issued on Sep. 30, 2008, which application claims priority to disorder is an issue for only a small portion of the population. U.S. Provisional Patent Application Ser. No. 60/616,393, 0008. In addition to those individuals who satisfy a strict filed Oct. 5, 2004 by Gadde et al., and entitled “COMPOSI definition of medical obesity, a significant portion of the adult TIONS OF AN ANTICONVULSANT AND AN ANTIPSY population is overweight. These overweight individuals CHOTIC DRUG AND METHODS OF USING THE SAME would also benefit from the availability of an effective FOR AFFECTING WEIGHT LOSS, U.S. Provisional weight-loss composition. Therefore, there is an unmet need in Patent Application Ser. No. 60/567,896, filed May 3, 2004 by the art to provide pharmaceutical compositions that can affect Ranga Krishnan, and entitled “COMPOSITIONS FOR AFFECTING WEIGHT LOSS, U.S. Provisional Patent weight loss without having other adverse side effects. Application Ser. No. 60/535,800, filed Jan. 13, 2004 by Gadde et al., and entitled “METHOD FOR REDUCING SUMMARY OF THE INVENTION WEIGHT GAIN RISK ASSOCIATED WITH ANTIDE 0009 Disclosed are compositions for affecting weight PRESSANT THERAPY,” and U.S. Provisional Patent Appli loss comprising a first compound and a second compound, cation Ser. No. 60/535,799, filed Jan. 13, 2004 by Gadde et where the first compound is a psychotherapeutic agent and al., and entitled “METHOD FOR REDUCING WEIGHT the second compound is an anticonvulsant. GAIN RISK ASSOCIATED WITH ANTIDEPRESSANT 0010 Disclosed are also methods of reducing the risk of THERAPY,” all of which are incorporated herein by refer weight gain associated with the use of antidepressants or ence in their entirety. other antipsychotic drugs.

BACKGROUND OF THE INVENTION DETAILED DESCRIPTION OF THE PREFERRED 0002 1. Field of the Invention EMBODIMENT 0003. The present invention is in the field of pharmaceu 0011 Newer generation antidepressants seem less likely tical compositions and methods for the treatment of obesity to be associated with cardiovascular side effects and toxicity and for affecting weight loss in individuals. associated with older generation antidepressants. Such as tri 0004 2. Description of the Related Art cyclic antidepressants or monoamine oxidase inhibitors 0005. Obesity is a disorder characterized by the accumu (MAOIs). Currently, newer generation antidepressants lation of excess fat in the body. Obesity has been recognized include selective serotonin reuptake inhibitors (e.g., fluoxet as one of the leading causes of disease and is emerging as a ine, fluvoxamine, Sertraline, paroxetine, citalopram, and esci global problem. Increased instances of complications such as talopram), Venlafaxine, dulloxetine, nefazodone, mianserin hypertension, non-insulin dependent diabetes mellitus, arte setiptiline, Vicqualine traZodone, cianopramine, and mirtaza riosclerosis, dyslipidemia, certain forms of cancer, sleep pine. Weight gain has been a major concern with certain of the apnea, and osteoarthritis have been related to increased newer antidepressants, particularly, with paroxetine instances of obesity in the general population. (PAXIL(R) PAXIL CR(R)) and mirtazapine (Fava, J. Clin. 0006 Obesity has been defined in terms of body mass Psych. 61 (suppl. 11):37-41 (2000); Carpenter et al. J. Clin. index (BMI). BMI is calculated as weight (kg)/height (m). Psych. 60:45-49 (1999): Aronne et al., J. Clin. Psych. 64 According to the guidelines of the U.S. Centers for Disease (suppl. 8):22-29 (2003), both of which are incorporated by Control and Prevention (CDC), and the World Health Orga reference herein in their entirety). A large proportion of nization (WHO) (World Health Organization. Physical sta patients treated with paroxetine, mirtazapine, and other anti tus: The use and interpretation of anthropometry. Geneva, depressants, such as venlafaxine (EFFEXORR, EFFEXOR Switzerland: World Health Organization 1995. WHO Techni XRR), gain a significant amount of weight. Most of these cal Report Series), for adults over 20 years old, BMI falls into patients find it difficult to lose the weight gained as a result of one of these categories: below 18.5 is considered under treatment, even after discontinuing use of the particular anti weight, 18.5-24.9 is considered normal, 25.0-29.9 is consid depressant. Weight gain is unacceptable in patients and a ered overweight, and 30.0 and above is considered obese. major reason for noncompliance with antidepressant therapy 0007 Prior to 1994, obesity was generally considered a (Cash et al., Percep. Motor Skills 90:453-456 (2000): Desh psychological problem. The discovery of the adipostatic hor mukh etal, Cleveland Clinic J.Med. 70:614-618 (2003), both mone leptin in 1994 (Zhang et al., “Positional cloning of the of which are incorporated by reference herein in their mouse obese gene and its human homologue.” Nature 1994: entirety). Without being bound by any particular theory, it is 372:425-432) brought forth the realization that, in certain believed that potential mechanisms for the observed weight cases, obesity may have a biochemical basis. A corollary to gain include histamine H1 receptor antagonism for mirtaza this realization was the idea that the treatment of obesity may pine, and anticholinergic effects in the case of paroxetine. beachieved by chemical approaches. Since then, a number of 0012 Zonisamide is a marketed anticonvulsant indicated such chemical treatments have entered the market. The most as adjunctive therapy for adults with partial onset seizures. famous of these attempts was the introduction of Fen-Phen, a Without being bound by any particular theory, it is believed US 2009/00181 15 A1 Jan. 15, 2009

that the mechanism of antiepileptic activity appears to be: 1) lithium citrate. In some embodiments, the lithium drug is in Sodium-channel blocking; and, 2) reduction of inward T-type an extended release formulation. calcium currents. In addition, Zonisamide binds to the GABA/ 0019. In some embodiments, the present invention is benzodiazepine receptor complex without producing change directed to compositions comprising Zonisamide and a salt of in chloride flux. Further, Zonisamide facilitates serotonergic lithium, as described herein and in formulations described and dopaminergic neurotransmission and possesses a weak herein. In other embodiments, the present invention is inhibitory effect on carbonic anhydrase. directed to compositions comprising Zonisamide and Valproic 00.13 Zonisamide has been shown to cause significant acid, or a pharmaceutically acceptable salt, Such as different weight loss (comparable to marketed weight loss medica salts of valproate, ester, amide, or prodrugs thereof. tions) in patients presenting with primary obesity (Gadde et 0020. In certain embodiments, the antidepressant is a al, JAMA 289:1820-1825 (2003), incorporated by reference compound of Formula I herein in its entirety). It has been postulated that it is the effect of Zonisamide on the CNS concentration of serotonin, dopamine and carbonic anhydrase that is responsible for this (I) effect. There is evidence that Zonisamide increases serotonin and dopamine synthesis rates (Hashiguti et al., J Neural Transm Gen Sect. 1993:93:213-223; Okada et al. Epilepsy N Res. 1992:13:113-119, both of which are incorporated by R6 R2 reference herein in their entirety). There is further evidence N Suggesting that Zonisamide stimulates dopamine D receptors R7 R3 (Okada et al. Epilepsy Res. 1995:22:193-205, incorporated by reference herein in its entirety). Zonisamide was well N tolerated, fatigue being the only side effect that occurred more R8 R4 frequently than with placebo treatment. Ro Rs 0014 Thus, the present inventors have determined that the use of anticonvulsants in general is effective in reducing or preventing the weight gain associated with the use of medi where cations such as antidepressants, particularly newer generation 0021 W is nitrogen, CH, oxygen, or sulfur; of antidepressants, antihistamines, and serotonin receptor 0022 R is selected from the group consisting of hydro antagonists, such as 5HT2 receptor antagonists. gen, optionally Substituted C. alkyl, optionally Substituted 00.15 Aspects of the present invention provide, at least in Cs cycloalkyl, optionally Substituted C- alkenyl, option part, methods of reducing the risk of weight gain associated ally Substituted C- alkynyl, optionally Substituted C with antidepressant therapy. These methods involve the use of alkoxyalkyl, and optionally Substituted aryland arylalkyl, weight-loss promoting anticonvulsants. The methods of the 0023. R. R. Ra, and Rs are each independently selected present invention are also effective against individuals who from the group consisting of hydrogen, halogen, optionally have gained weight irrespective of the use of antidepressants. Substituted C. alkyl, optionally substituted C. alkyloxy, 0016. Thus, in a first aspect, the present invention is optionally Substituted C- alkenyl, optionally Substituted directed to a composition for the treatment of obesity or for Calkynyl, optionally substituted C-alkoxyalkyl, option affecting weight loss comprising a first compound and a ally substituted C. alkylthio, perhaloalkyl, CN, COR second compound, where the first compound is a psycho CONHR, heteroalkyl, and NO; therapeutic agent and the second compound is an anticonvul 0024 R. R. Rs, and Ro, are each independently selected Sant from the group consisting of hydrogen, halogen, optionally 0017. In certain embodiments, the anticonvulsant is effec Substituted C. alkyl, optionally substituted C. alkyloxy, tive in reducing convulsions in a mammal. The mammal may optionally Substituted C- alkenyl, optionally Substituted be selected from the group consisting of mice, rats, rabbits, C- alkynyl, optionally Substituted C-alkoxyalkyl, option guinea pigs, dogs, cats, sheep,goats, cows, primates, such as ally substituted C. alkylthio, perhaloalkyl, CN, COR monkeys, chimpanzees, and apes, and humans. CONHR heteroalkyl, and NO. 0018. In some embodiments the psychotherapeutic agent 0025. The term “pharmaceutically acceptable salt” refers is an antidepressant, an antimigrane, an antibipolar, an anti to a formulation of a compound that does not cause significant mania drug, a mood stabilizer, or an antiepileptic. Examples irritation to an organism to which it is administered and does of antidepressants include paroxetine and mirtazapine. not abrogate the biological activity and properties of the Examples of antimigrane drugs include Sumatriptan, Zolmi compound. Pharmaceutical salts can be obtained by reacting triptan, elatriptan and other triptans. Examples of antibipolar a compound of the invention with inorganic acids Such as drugs include lithium, Valproate, carbameZepine, oxycar hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric bameZepine, lamotrogine, tiagabine, olanzapine, clozapine, acid, phosphoric acid, methanesulfonic acid, ethanesulfonic risperidone, quetiapine, aripiprazole, Ziprasidone, and benzo acid, p-toluenesulfonic acid, Salicylic acid and the like. Phar diazepines. In a Some embodiments, the psychotherapeutic maceutical salts can also be obtained by reacting a compound agent comprises a salt of lithium. In other embodiments, the of the invention with a base to form a salt such as an ammo psychotherapeutic agent is valproate, which includes both the nium salt, analkali metal salt, Such as a Sodium or a potassium salt of valproate and the free acid form of valproic acid. Also salt, an alkaline earth metal salt, such as a calcium or a included are pharmaceutically acceptable salts or prodrugs of magnesium salt, a salt of organic bases Such as dicyclohexy these drugs, extended release formulations of the above lamine, N-methyl-D-glucamine, tris(hydroxymethyl)methy drugs, as well as combinations of the above drugs. In some lamine, and salts thereof with amino acids such as arginine, embodiments, the lithium salt may be lithium carbonate or lysine, and the like. US 2009/00181 15 A1 Jan. 15, 2009

0026. A “prodrug” refers to an agent that is converted into composition for the treatment of obesity or for affecting the parent drug in vivo. Prodrugs are often useful because, in weight loss comprising Zonisarnide and paroxetine. In yet Some situations, they may be easier to administer than the another embodiment, the present invention is directed to a parent drug. They may, for instance, be bioavailable by oral composition for the treatment of obesity or for affecting administration whereas the parent is not. The prodrug may weight loss comprising Zonisarnide and Venlafaxine. also have improved solubility in pharmaceutical composi 0033. In certain embodiments, the present invention is tions over the parent drug, or may demonstrate increased directed to a Composition for affecting weight loss or for palatability or be easier to formulate. An example, without preventing weight gain comprising Zonisamide and mirtaza limitation, of a prodrug would be a compound of the present pine. In other embodiments, the present invention is directed invention which is administered as an ester (the “prodrug) to to a composition for affecting weight loss or for preventing facilitate transmittal across a cell membrane where water weight gain comprising bupropion and mirtazapine. In fur solubility is detrimental to mobility but which then is meta ther embodiments, the present invention is directed to a com bolically hydrolyzed to the carboxylic acid, the active entity, position for affecting weight loss or for preventing weight once inside the cell where water-solubility is beneficial. A gain comprising Zonisamide and setiptiline. In other embodi further example of a prodrug might be a short peptide ments, the present invention is directed to a composition for (polyaminoacid) bonded to an acid group where the peptide is affecting weight loss or for preventing weight gain compris metabolized to provide the active moiety. ing bupropion and Setiptiline. In additional embodiments, the 0027. In another embodiment, the antidepressant is a tri present invention is directed to a composition for affecting cyclic antidepressants. Examples of tricyclic antidepressants weight loss or for preventing weight gain comprising Zonisa include, but are not limited to, imipramine, desipramine, mide, bupropion, and mirtazapine. In yet other embodiments, trimipramine, nortriptyline, clomipramine, doxepin, amitrip the present invention is directed to a composition for affecting tyline, maprotiline, protriptyline, dothiapen, setiptiline, weight loss or for preventing weight gain comprising Zonisa cianopramine, and maprotiline. Maprotiline, a very effective mide, bupropion, and Setiptiline. antidepressant, is not used widely because it carries risk of 0034. Throughout the present disclosure, when a particu seizures. The combination of maprotiline and Zonisamide or lar compound is mentioned by name, for example, Zonisa other anticonvulsants has the added benefit of reducing the mide, bupropion, Setiptiline, mirtazapine, or valproate, it is risk of seizures, in addition to reducing the risk of weight gain understood that the scope of the present disclosure encom due to the use of the antidepressant. The same is also true for passes pharmaceutically acceptable salts, esters, amides, or combining Zonisamide with clomipramine, another tricyclic prodrugs of the named compound. Also, if the named com associated with a relatively higher risk of seizures. pound comprises a chiral center, the scope of the present 0028. In further embodiments, the antidepressant is a disclosure also includes compositions comprising the race monoamine oxidase inhibitor (MAO inhibitor). Examples of mic mixture of the two enantiomers, as well as compositions MAO inhibitors include, but are not limited to, phenelzine comprising eachenantiomer individually substantially free of (Nardil.R.), tranylcypromine (Parnate(R), isocarboxazid (Mar the other enantiomer. Thus, for example, contemplated herein plan.R.), moclobemide (Aurorix(R), brofaromine , is a composition comprising the Senantiomer Substantially cimoxatone, clorgyline, and lazabemide. free of the Renantiomer, or a composition comprising the R 0029. In certain embodiments, the antihistamine is one of enantiomer substantially free of the Senantiomer. By “sub setiptiline, teciptiline, ORG 8282 (Organon, Netherlands), or stantially free’ it is meant that the composition comprises less MO 8282 (Mochida, Japan). than 10%, or less than 8%, or less than 5%, or less than 3%, or 0030. In some embodiments, the 5HT, receptor antago less than 1% of the minor enantiomer. If the named compound nist is selected from colozapine, N-desmethylclozapine, and comprises more than one chiral center, the scope of the clozapine-N-oxide. present disclosure also includes compositions comprising a 0031. In some embodiments, the second compound is an mixture of the various diastereomers, as well as compositions anticonvulsant. Examples of anticonvulsants include barbitu comprising each diastereomer Substantially free of the other rates, benzodiazepines, GABA analogues, hydantoins, mis diastereomers. Thus, for example, commercially available cellaneous anticonvulsants, phenyltriazines, and Succinim mirtazapine is a racemic mixture comprising two separate ides. An example of a barbiturate includes pentobarbital. enantiomers. The recitation of “mirtazapine' throughout this Examples of benzodiazepines include clonazepam, cloraZe disclosure includes compositions that comprise the racemic pate, benzodiazepine, and diazepam. Examples of GABA mixture of mirtazapine, the compositions that comprise the analogues include tiagabine, pregabalin, and gabapentin. (+) enantiomer Substantially free of the (-) enantiomer, and Examples of hydantoins include fosphenytoin, phenytoin, the compositions that comprise the (-) enantiomer Substan and 5.5-Diphenylhydantoin. Examples of miscellaneous anti tially free of the (+) enantiomer. convulsants include carbarnazepine, valproate, valproic acid, 0035. In another aspect, the present invention relates to a divalproex, felbamate, levetiracetam, carbamazepine, topira method of affecting weight loss, comprising identifying an mate, oXcarbazepine, and Zonisamide. An example of a phe individual in need thereof and treating that individual with a nyltriazine is lamotrigine. Examples of Succinimides include psychotherapeutic agent and an anticonvulsant. The psycho methSuximide and ethoSuximide. Also included are extended therapeutic agent and the anticonvulsant are as described release formulations of the above drugs, pharmaceutically above. acceptable salts or prodrugs thereof, as well as combinations 0036. In certain embodiments, the individual has a body of the above drugs. mass index (BMI) greater than 25. In other embodiments, the 0032. In one embodiment, the present invention is directed individual has a BMI greater than 30 In still other embodi to a composition for the treatment of obesity or for affecting ments, the individual has a BMI greater than 40. However, in weight loss comprising Zonisamide and mirtazapine. In some embodiments, the individual may have a BMI less than another embodiment, the present invention is directed to a 25. In some of these embodiments, it may be beneficial for US 2009/00181 15 A1 Jan. 15, 2009 health or cosmetic purposes to affect weight loss, thereby prising identifying an individual in need thereof and treating reducing the BMI even farther. In some embodiments, the that individual by administering to the individual a first com individual has reached the above BMI as the result of antide pound and a second compound, where the first compound is a pressant therapy. In other embodiments, the individual has psychotherapeutic agent and the second compound is a anti reached the above BMI without the use of antidepressants. convulsant. 0037. In some embodiments, the treating step of the above 0046. In some embodiments the first compound and the method comprises administering to the individual a first com second compound are administered nearly simultaneously. In pound and a second compound, where the first compound is a other embodiments the first compound is administered prior psychotherapeutic agent and the second compound is a anti to the second compound. In yet other embodiments, the first convulsant. compound is administered Subsequent to the second com 0038. In some embodiments the first compound and the pound. second compound are administered more or less simulta 0047. In certain embodiments, the first compound is neously. In other embodiments the first compound is admin Zonisamide and the second compound is mirtazapine. In other istered prior to the second compound. In yet other embodi embodiments, the first compound is bupropion and the sec ments, the first compound is administered Subsequent to the ond compound is mirtazapine. In further embodiments, the second compound. first compound is Zonisamide and the second compound is 0039. In certain embodiments, the first compound and the setiptiline. In other embodiments, the first compound is second compound are administered individually. In other bupropion and the second compound is setiptiline. In addi embodiments, the first compound and the second compound tional embodiments, the first compound is a combination of are covalently linked to each other Such that they form a single Zonisamide and bupropion and the second compound is mir chemical entity. The single chemical entity is then digested tazapine. In yet other embodiments, the first compound is a and is metabolized into two separate physiologically active combination of Zonisamide and bupropion and the second chemical entities; one of which is the first compound and the compound is setliptiline. other one is the second compound. 0048. In another aspect, the present invention relates to a 0040. In certain embodiments, the first compound is method of increasing energy expenditure in an individual Zonisamide and the second compound is mirtazapine. In other comprising identifying an individual in need thereof and embodiments, the first compound is bupropion and the sec treating that individual by administering to the individual a ond compound is mirtazapine. In further embodiments, the first compound and a second compound, where the first com first compound is Zonisamide and the second compound is pound is a psychotherapeutic agent and the second compound setiptiline. In other embodiments, the first compound is is a anticonvulsant. bupropion and the second compound is setiptiline. In addi 0049. In some embodiments the first compound and the tional embodiments, the first compound is a combination of second compound are administered nearly simultaneously. In Zonisamide and bupropion and the second compound is mir other embodiments the first compound is administered prior tazapine. In yet other embodiments, the first compound is a to the second compound. In yet other embodiments, the first combination of Zonisamide and bupropion and the second compound is administered Subsequent to the second com compound is setliptiline. pound. 0041. In some embodiments, the first compound is Zonisa 0050. In certain embodiments disclosed herein, an indi mide and the second compound is a salt of lithium, as vidual is given a pharmaceutical composition comprising a described herein and in formulations described herein. In combination of two or more compounds to affect weight loss. other embodiments, the first compound is Zonisamide and the In some of these embodiments, each compound is a separate second compound is valproic acid, or a pharmaceutically chemical entity. However, in other embodiments, the two acceptable salt, such as different salts of valproate, ester, compounds are joined together by a chemical linkage, such as amide, or pro drugs thereof. a covalent bond, so that the two different compounds form 0042. In some embodiments, the first compound is topira separate parts of the same molecule. The chemical linkage is mate and the second compound is a salt of lithium, as selected such that after entry into the body, the linkage is described herein and in formulations described herein. In broken, such as by enzymatic action, acid hydrolysis, base other embodiments, the first compound is topiramate and the hydrolysis, or the like, and the two separate compounds are second compound is valproic acid, or a pharmaceutically then formed. acceptable salt, such as different salts of valproate, ester, 0051 Aspects of the present invention also relate to meth amide, or prodrugs thereof. ods of reducing the risk of weight gain associated with the 0043. In another aspect, the present invention relates to a administration of antidepressants, antihistamines, or seroto method of increasing Satiety in an individual comprising nin receptor antagonists. Other aspects of the invention fur identifying an individual in need thereof and treating that ther relate to methods of minimizing metabolic risk factors individual with a first compound and a second compound, associated with weight gain, such as hypertension, diabetes where the first compound is a psychotherapeutic agent and and dyslipidaemia. In one embodiment, the methods com the second compound is an anticonvulsant. prise administering to a mammal receiving an antidepressant 0044. In some embodiments the first compound and the an amount of Zonisamide, or other weight-loss promoting second compound are administered nearly simultaneously. In anticonvulsant, Sufficient to reduce the weight gain risk asso other embodiments the first compound is administered prior ciated with the antidepressant. In an alternative embodiment, to the second compound. In yet other embodiments, the first the methods comprise administering to mammal receiving an compound is administered Subsequent to the second com antidepressant a combination of Zonisamide or topiramate, or pound. other weight-loss promoting anticonvulsant (including 0045. In yet another aspect, the present invention relates to agents that block kainate/AMPA (D.L-C.-amino-3-hydroxy a method of Suppressing the appetite of an individual com 5-methyl-isoxazole propionic acid) subtype glutamate recep US 2009/00181 15 A1 Jan. 15, 2009 tors), and bupropion, or other compound that enhances the herein can vary with the patient, the antidepressant that the activity of norepinephrine and/or dopamine via uptake inhi patient is receiving, the route of administration and the result bition or other mechanism, in an amount Sufficient to reduce sought. Optimum dosing regimens for particular patients can the weight gain risk associated with the antidepressant. be readily determined by one skilled in the art. 0052. In certain embodiments, methods of the present 0058. In accordance with the invention, the combination invention are directed to reducing the risk of weight gain in an of for example, Zonisamide or topiramate and bupropion individual who already is on antidepressant therapy, or is (including Sustained release preparations) provides an effec about to begin antidepressant therapy. In these embodiments, tive means of minimizing metabolic risks associated with in addition to the antidepressant, the individual is adminis weight gain and/or antidepressant use (e.g., type II diabetes). tered a composition comprising an anticonvulsant and a psy The combination can be more effective than, for example, chotherapeutic drug, as described herein, where the psycho Zonisamide or topiramate treatment alone and with fewer side therapeutic drug is not an antidepressant. Thus, in some effects. Neuropharmacologically, all three major nerve trans embodiments, the individual who is taking mirtazapine or mitters that regulate appetite and weight, i.e., serotonin, nore setiptiline is administered a composition comprising Zonisa pinephrine and dopamine, are targeted with the combination mide or a composition comprising Zonisamide and bupro of for example, bupropion and Zonisamide or topiramate. pion. In other embodiments, the individual who is taking Side effects of, for example, Zonisarnide or topiramate (Such mirtazapine or setiptiline is administered a composition com as Somnolence, psychomotor slowing, cognitive impairment, prising Zonisamide or a composition comprising Zonisamide fatigue and depression) can be offset by insomnia, activation, and valproate. In further embodiments, the individual who is psychomotor agitation and antidepressant effects of for taking mirtazapine or setliptiline is administered a composi example, bupropion. On the other hand, Zonisamide or topi tion comprising Zonisamide or a composition comprising ramate, for example, can reduce the seizure risk associated Zonisamide and Venlafaxine. with, for example, bupropion. Lower doses of both types of 0053. In certain embodiments, the weight gain risk-reduc medication can be used in the combination treatment, thereby ing agents for use in the methods of the present invention further reducing the overall side effect burden. include Zonisamide or topiramate (and pharmaceutically 0059. With regard to the pharmacokinetics of Zonisamide, acceptable salts thereof). In other embodiments, other meth its renal excretion and minimal potential for inhibition or ane-sulfonamide derivatives, such as those described in U.S. induction of hepatic microsomal enzymes, are favorable Pat. No. 4,172,896, or other sulfamates (including sulfamate qualities in the concept of combination use with antidepres Substituted monosaccharides), such as those described in sants, particularly newer generation antidepressants. U.S. Pat. No. 4.513,006, incorporated by reference herein in 0060. In another aspect, the invention relates to a pharma its entirety, are used. ceutical composition comprising a combination of a psycho 0054. In further embodiments, the weight gain risk-reduc therapeutic agent and an anticonvulsant, as described above, ing agent is bupropion; while in other embodiments, com or comprising a linked molecule, as described herein, and a pounds disclosed in U.S. Pat. No. 3,819,706 and 3,885,046, physiologically acceptable carrier, diluent, or excipient, or a both of which are incorporated by reference herein in their combination thereof. entirety, are used. In additional embodiments, the weight gain 0061. Details of some embodiments of the appropriate risk-reducing agent is a compound that enhances the activity routes of administration and compositions Suitable for same of norepinephrine and/or dopamine, such as by reuptake inhi can be foundin, for example, U.S. Pat. Nos. 6,110,973, 5,763, bition or other mechanism. All of the above-mentioned U.S. 493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172, patents are. 896, as well as in patents cited therein, all of which are 0055 Compounds that enhance the activity of norepi incorporated by reference herein in their entirety, including nephrine and/or dopamine include norepinephrine agonists, any drawings. Such as phendimetrazine and benzphetamine; norepinephrine 0062. The term “pharmaceutical composition” refers to a reuptake inhibitors such as atomoxetine, bupropion, radafax mixture of a compound of the invention with other chemical ine, thionisoxetine, and reboxetine; dopamine agonists, such components, such as diluents or carriers. The pharmaceutical as cabergoline, amantadine, lisuride, pergolide, ropinirole, composition facilitates administration of the compound to an pranipexole, and bromocriptine; norepinephrine releasers, organism. Multiple techniques of administering a compound for example diethylpropion; a mixed dopamine/norepineph exist in the art including, but not limited to, oral, injection, rine reuptake inhibitor, for example, bupropion; a combina aerosol, parenteral, and topical administration. Pharmaceuti tion of a dopamine reuptake inhibitor and a norepinephrine cal compositions can also be obtained by reacting compounds reuptake inhibitor, e.g. bupropion and mazindol; or a combi with inorganic or organic acids such as hydrochloric acid, nation of a selective serotonin reuptake inhibitor (SSRI) and hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, a norepinephrine reuptake inhibitor, such as Sibutramine, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic Venlafaxine, and dulloxetine. acid, salicylic acid and the like. 0056 Mammals suitable for treatment in accordance with 0063. The term “carrier defines a chemical compound the instant invention can be receiving any antidepressant that facilitates the incorporation of a compound into cells or associated with weight gain. Typically, however, the antide tissues. For example dimethyl sulfoxide (DMSO) is a com pressant is a newer generation antidepressant (e.g., a selective monly utilized carrier as it facilitates the uptake of many serotonin uptake inhibitor (e.g., fluoxetine, fluvoxamine, Ser organic compounds into the cells or tissues of an organism. traline, paroxetine, citalopram, and escitalopram), Venlafax 0064. The term "diluent defines chemical compounds ine, nefazodone, and mirtazapine)), particularly, paroxetine diluted in water that will dissolve the compound of interest as or mirtazapine. well as stabilize the biologically active form of the com 0057 The amount of weight gain risk-reducing agent(s) pound. Salts dissolved in buffered solutions are utilized as administered in the pharmaceutical compositions described diluents in the art. One commonly used buffered solution is US 2009/00181 15 A1 Jan. 15, 2009

phosphate buffered saline because it mimics the salt condi Sorbitol; cellulose preparations such as, for example, maize tions of human blood. Since buffer salts can control the pH of starch, wheat starch, rice starch, potato starch, gelatin, gum a solution at low concentrations, a buffered diluent rarely tragacanth, methyl cellulose, hydroxypropylmethyl-cellu modifies the biological activity of a compound. lose, Sodium carboxymethylcellulose, and/or polyvinylpyr 0065. The term “physiologically acceptable' defines a rolidone (PVP). If desired, disintegrating agents may be carrier or diluent that does not abrogate the biological activity added, such as the cross-linked polyvinyl pyrrolidone, agar, and properties of the compound. or alginic acid or a salt thereof Such as sodium alginate. 0066. The pharmaceutical compositions described herein 0073 Dragee cores are provided with suitable coatings. can be administered to a human patient perse, or in pharma For this purpose, concentrated Sugar Solutions may be used, ceutical compositions where they are mixed with other active which may optionally contain gum arabic, talc, polyvinyl ingredients, as in combination therapy, or Suitable carriers or pyrrolidone, carbopol gel, polyethylene glycol, and/or tita excipient(s). Techniques for formulation and administration nium dioxide, lacquer Solutions, and Suitable organic solvents of the compounds of the instant application may be found in or solvent mixtures. Dyestuffs or pigments may be added to “Remington's Pharmaceutical Sciences. Mack Publishing the tablets or dragee coatings for identification or to charac Co., Easton, Pa., 18th edition, 1990. terize different combinations of active compound doses. 0067 Suitable routes of administration may, for example, 0074 Pharmaceutical preparations which can be used include oral, rectal, transmucosal, or intestinal administra orally, including Sublingually, which include include push-fit tion; parenteral delivery, including intramuscular, Subcutane capsules made of gelatin, as well as soft, sealed capsules ous, intravenous, intramedullary injections, as well as intrath made of gelatin and a plasticizer, such as glycerol or Sorbitol, ecal, direct intraventricular, intraperitoneal, intranasal, or The push-fit capsules can contain the active ingredients in intraocular injections. admixture with filler Such as lactose, binders such as starches, 0068 Alternately, one may administer the compound in a and/or lubricants such as talc or magnesium Stearate and, local rather than systemic manner, for example, via injection optionally, stabilizers. In soft capsules, the active compounds of the compound directly in the renal or cardiac area, often in may be dissolved or Suspended in Suitable liquids, such as a depot or Sustained release formulation. Furthermore, one fatty oils, liquid paraffin, or liquid polyethylene glycols. In may administer the drug in a targeted drug delivery system, addition, stabilizers may be added. All formulations for oral for example, in a liposome coated with a tissue-specific anti administration should be in dosages suitable for Such admin body. The liposomes will be targeted to and taken up selec istration. tively by the organ. 0075 For buccal administration, the compositions may 0069. The pharmaceutical compositions of the present take the form of tablets or lozenges formulated in conven invention may be manufactured in a manner that is itself tional manner. known, e.g., by means of conventional mixing, dissolving, 0076 For administration by inhalation, the compounds for granulating, dragee-making, levigating, emulsifying, encap use according to the present invention are conveniently deliv Sulating, entrapping or tabletting processes. ered in the form of an aerosol spray presentation from pres 0070 Pharmaceutical compositions for use in accordance surized packs or a nebulizer, with the use of a suitable pro with the present invention thus may beformulated in conven pellant, C.9. dichlorodifluoromethane, tional manner using one or more physiologically acceptable trichlorofluoromethane, dichlorotetrafluoroethane, carbon carriers comprising excipients and auxiliaries which facilitate dioxide, or other Suitable gas. In the case of a pressurized processing of the active compounds into preparations which aerosol the dosage unit may be determined by providing a can be used pharmaceutically. Proper formulation is depen valve to deliverametered amount. Capsules and cartridges of dent upon the route of administration chosen. Any of the e.g., gelatin for use in an inhaler or insufflator may be formu well-known techniques, carriers, and excipients may be used lated containing a powder mix of the compoundanda Suitable as Suitable and as understood in the art; e.g., in Remington's powder base such as lactose or starch. Pharmaceutical Sciences, above. 0077. The compounds may be formulated for parenteral 0071. For injection, the agents of the invention may be administration by injection, e.g., by bolus injection or con formulated in aqueous solutions, preferably in physiologi tinuous infusion. Formulations for injection may be presented cally compatible buffers such as Hanks’s solution, Ringer's in unit dosage form, e.g., in ampoules or in multi-dose con Solution, or physiological Saline buffer. For transmucosal tainers, with an added preservative. The compositions may administration, penetrants appropriate to the barrier to be take Such forms as Suspensions, solutions or emulsions in oily permeated are used in the formulation. Such penetrants are or aqueous vehicles, and may contain formulatory agents generally known in the art. Such as Suspending, stabilizing and/or dispersing agents. 0072 For oral administration, the compounds can be for 0078 Pharmaceutical formulations for parenteral admin mulated readily by combining the active compounds with istration include aqueous solutions of the active compounds pharmaceutically acceptable carriers well known in the art. in water-soluble form. Additionally, suspensions of the active Such carriers enable the compounds of the invention to be compounds may be prepared as appropriate oily injection formulated as tablets, pills, dragees, capsules, liquids, gels, suspensions. Suitable lipophilic solvents or vehicles include syrups, slurries, Suspensions and the like, for oral ingestion by fatty oils such as sesame oil, or synthetic fatty acid esters, a patient to be treated. Pharmaceutical preparations for oral Such as ethyl oleate or triglycerides, or liposomes. Aqueous use can be obtained by mixing one or more solid excipient injection Suspensions may contain Substances which increase with pharmaceutical combination of the invention, optionally the Viscosity of the Suspension, Such as Sodium carboxym grinding the resulting mixture, and processing the mixture of ethyl cellulose, sorbitol, or dextran. Optionally, the suspen granules, after adding Suitable auxiliaries, if desired, to obtain sion may also contain Suitable stabilizers or agents which tablets or dragee cores. Suitable excipients are, in particular, increase the solubility of the compounds to allow for the fillers such as Sugars, including lactose, Sucrose, mannitol, or preparation of highly concentrated Solutions. US 2009/00181 15 A1 Jan. 15, 2009

0079 Alternatively, the active ingredient may be in pow therapeutically effective amount is well within the capability der form for constitution with a suitable vehicle, e.g., sterile of those skilled in the art, especially in light of the detailed pyrogen-free water, before use. disclosure provided herein. 0080. The compounds may also be formulated in rectal 0086. The exact formulation, route of administration and compositions such as Suppositories or retention enemas, e.g., dosage for the pharmaceutical compositions of the present containing conventional Suppository bases such as cocoa but invention can be chosen by the individual physician in view of ter or other glycerides. the patient's condition. (See e.g., Finglet al 1975, in “The 0081. In addition to the formulations described previously, Pharmacological Basis of Therapeutics' Ch. 1 p. 1). Typi the compounds may also be formulated as a depot prepara cally, the dose range of the composition administered to the tion. Such long acting formulations may be administered by patient can be from about 0.5 to 1000 mg/kg of the patient’s implantation (for example Subcutaneously or intramuscu body weight. The dosage may be a single one or a series of larly) or by intramuscular injection. Thus, for example, the two or more given in the course of one or more days, as is compounds may be formulated with Suitable polymeric or needed by the patient. Note that for almost all of the specific hydrophobic materials (for example as an emulsion in an compounds mentioned in the present disclosure, human dos acceptable oil) or ion exchange resins, or as sparingly soluble ages for treatment of at least some condition have been estab derivatives, for example, as a sparingly soluble salt. lished. Thus, in most instances, the present invention will use 0082. A pharmaceutical carrier for the hydrophobic com those same dosages, or dosages that are between about 0.1% pounds of the invention is a cosolvent system comprising and 500%, more preferably between about 25% and 250% of benzyl alcohol, a nonpolar Surfactant, a water-miscible the established human dosage. Where no human dosage is organic polymer, and an aqueous phase. A common cosolvent established, as will be the case for newly-discovered pharma system used is the VPD co-solvent system, which is a solution ceutical compounds, a Suitable human dosage can be inferred of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant from EDso or IDso values, or other appropriate values derived Polysorbate 80TM, and 65% w/v polyethylene glycol 300, from in vitro or in vivo studies, as qualified by toxicity studies made up to volume in absolute ethanol. Naturally, the propor and efficacy studies in animals. tions of a co-solvent system may be varied considerably with I0087 Although the exact dosage will be determined on a out destroying its solubility and toxicity characteristics. Fur drug-by-drug basis, in most cases, some generalizations thermore, the identity of the co-solvent components may be regarding the dosage can be made. The daily dosage regimen varied: for example, other low-toxicity nonpolar Surfactants for an adult human patient may be, for example, an oral dose may be used instead of POLYSORBATE 80TM; the fraction of between 0.1 mg and 6000mg of eachingredient, preferably size of polyethylene glycol may be varied; other biocompat between 1 mg and 5000 mg, e.g. 25 to 5000 mg or an intra ible polymers may replace polyethylene glycol, e.g., polyvi venous, Subcutaneous, or intramuscular dose of each ingre nyl pyrrolidone; and other Sugars or polysaccharides may dient between 0.01 mg and 100 mg, preferably between 0.1 substitute for dextrose. mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the 0083. Alternatively, other delivery systems for hydropho pharmaceutical compositions of the present invention or a bic pharmaceutical compounds may be employed. Lipo pharmaceutically acceptable salt thereof calculated as the Somes and emulsions are well known examples of delivery free base, the composition being administered 1 to 4 times per vehicles or carriers for hydrophobic drugs. Certain organic day. Alternatively the compositions of the invention may be Solvents such as dimethylsulfoxide also may be employed, administered by continuous intravenous infusion, preferably although usually at the cost of greater toxicity. Additionally, at a dose of each ingredient up to 400 mg per day. Thus, the the compounds may be delivered using a Sustained-release total daily dosage by oral administration of each ingredient system, Such as semipermeable matrices of Solid hydropho will typically be in the range 1 to 2500 mg and the total daily bic polymers containing the therapeutic agent. Various Sus dosage by parenteral administration will typically be in the tained-release materials have been established and are well range 0.1 to 400 mg. Suitably the compounds will be admin known by those skilled in the art. Sustained-release capsules istered for a period of continuous therapy, for example for a may, depending on their chemical nature, release the com week or more, or for months or years. pounds for a few weeks up to over 100 days. Depending on the I0088. In some embodiments, the dosage range for lithium chemical nature and the biological stability of the therapeutic carbonate, for an oral dose, will result in blood levels of reagent, additional strategies for protein stabilization may be lithium being between about 0.5 and about 1.5 meq/1. In a employed. preferred embodiment, the lithium carbonate dosage range, 0084. Many of the compounds used in the pharmaceutical for an oral dose, will be about 900 mg/day. combinations of the invention may be provided as salts with I0089. In certain embodiments, the dosage range for val pharmaceutically compatible counterions. Pharmaceutically proate, for an oral dose, is in the range of about 250 to about compatible salts may be formed with many acids, including 5000 mg/day. In a preferred embodiment, the valproate dos but not limited to hydrochloric, Sulfuric, acetic, lactic, tar age range, for an oral dose, will be about 1500 mg/day. taric, malic, succinic, etc. Salts tend to be more soluble in 0090. In further embodiments, the dosage range for aqueous or other protonic solvents than are the corresponding Zonisamide, for an oral dose, is in the range of about 25 to free acid or base forms. about 600 mg per day. In some embodiments, the dosage is 25 0085 Pharmaceutical compositions suitable for use in the mg per day. In other embodiments, the dosage is 50 mg per present invention include compositions where the active day. In yet other embodiments, the dosage is 100 mg per day. ingredients are contained in an amount effective to achieve its 0091. In further embodiments, the dosage range for intended purpose. More specifically, a therapeutically effec mitrazepine, for an oral dose, is in the range of about 5 to tive amount means an amount of compound effective to pre about 500 mg per day. In some embodiments, the dosage is 8 vent, alleviate or ameliorate symptoms of disease or prolong mg per day. In other embodiments, the dosage is 16 mg per the survival of the subject being treated. Determination of a day. In yet other embodiments, the dosage is 32 mg per day. In US 2009/00181 15 A1 Jan. 15, 2009

Some embodiments, the dosage is 15 mg per day. In other Some Embodiments of the Invention embodiments, the dosage is 30 mg per day. In yet other 0100 Some of the embodiments of the present invention embodiments, the dosage is 45 mg per day. are as follows: 0092. In other embodiments, the dosage range for ven 0101. In the first embodiment, the invention relates to a lafaxinor Venlafaxin XR, for an oral dose, is in the range of composition for affecting weight loss comprising a first com about 20 mg to about 600 mg per day. In some embodiments, pound and a second compound, wherein said first compound the dosage is 25 mg per day. In other embodiments, the is a psychotherapeutic agent and said second compound is an dosage is 37.5 mg per day. In yet other embodiments, the anticonvulsant. dosage is 50 mg per day. In some embodiments, the dosage is 0102. In the second embodiment, the invention relates to 75 mg per day. In other embodiments, the dosage is 100 mg the composition of the first embodiment, wherein said psy per day. In yet other embodiments, the dosage is 150 mg per chotherapeutic agent is selected from the group consisting of day. lithium carbonate, lithium citrate, valproate, mixtures 0093. Dosage amount and interval may be adjusted indi thereof, and pharmaceutically acceptable salts or prodrugs vidually to provide plasma levels of the active moiety which thereof. are sufficient to maintain the modulating effects, or minimal (0103. In the third embodiment, the invention relates to the composition of the first embodiment, wherein said second effective concentration (MEC). The MEC will vary for each compound is selected from the group consisting of a barbitu compound but can be estimated from in vitro data. Dosages rate, benzodiazepine, GABA analogue, hydantoins, anticon necessary to achieve the MEC will depend on individual Vulsant, phenyltriazine, Succinimide, pharmaceutically characteristics and route of administration. However, HPLC acceptable salts or prodrugs thereof, and combinations assays or bioassays can be used to determine plasma concen thereof. trations. 0104. In the fourth embodiment, the invention relates to 0094 Dosage intervals can also be determined using MEC the composition of the third embodiment, wherein said bar value. Compositions should be administered using a regimen biturate is pentobarbital or pharmaceutically acceptable salts that maintains plasma levels above the MEC for 10-90% of or prodrugs thereof. the time, preferably between 30-90% and most preferably 0105. In the fifth embodiment, the invention relates to the between 50-90%. composition of the third embodiment, wherein said benzodi azepine is selected from the group consisting of clonazepam, 0095. In cases of local administration or selective uptake, alprazolam, chlordiazepoxide, cloraZepate, diazepam, the effective local concentration of the drug may not be halazepam, lorazepam, oxazepam, prazepam, flurazepam, related to plasma concentration. temazepam, triazolam, pharmaceutically acceptable salts or 0096. The amount of composition administered will, of prodrugs thereof, and combinations thereof course, be dependent on the Subject being treated, on the 0106. In the sixth embodiment, the invention relates to the subject's weight, the severity of the affliction, the manner of composition of the third embodiment, wherein said GABA administration and the judgment of the prescribing physician. analogue is selected from the group consisting of tiagabine, 0097. The compositions may, if desired, be presented in a gabapentin, pregabalin, pharmaceutically acceptable salts or pack or dispenser device which may contain one or more unit prodrugs thereof, and combinations thereof. dosage forms containing the active ingredient. The pack may 0107. In the seventh embodiment, the invention relates to for example comprise metal or plastic foil. Such as a blister the composition of the third embodiment, wherein said pack. The pack or dispenser device may be accompanied by hydantoin is selected from the group consisting of fospheny instructions for administration. The pack or dispenser may toin, phenytoin, 5.5-Diphenylhydantoin, pharmaceutically also be accompanied with a notice associated with the con acceptable salts or prodrugs thereof, and combinations tainer in form prescribed by a governmental agency regulat thereof. ing the manufacture, use, or sale of pharmaceuticals, which 0108. In the eighth embodiment, the invention relates to notice is reflective of approval by the agency of the form of the the composition of the third embodiment, wherein said mis drug for human or veterinary administration. Such notice, for cellaneous anticonvulsant is selected from the group consist example, may be the labeling approved by the U.S. Food and ing of carbamazepine, Valproate, valproic acid, divalproex, Drug Administration for prescription drugs, or the approved felbamate, levetiracetam, carbamazepine, topiramate, oXcar product insert. Compositions comprising a compound of the baZepine, Zonisamide, pharmaceutically acceptable salts or invention formulated in a compatible pharmaceutical carrier prodrugs thereof, and combinations thereof. may also be prepared, placed in an appropriate container, and 0109. In the ninth embodiment, the invention relates to the composition of the third embodiment, wherein said phenyl labeled for treatment of an indicated condition. triazine is lamotrigine. 0098. It will be understood by those of skill in the art that 0110. In the tenth embodiment, the invention relates to the numerous and various modifications can be made without composition of the third embodiment, wherein said Succin departing from the spirit of the present invention. Therefore, imide is selected from the group consisting of methSuximide, it should be clearly understood that the forms of the present ethoSuximide, and combinations thereof. invention are illustrative only and are not intended to limit the 0111. In the eleventh embodiment, the invention relates to Scope of the present invention. the composition of the first embodiment, wherein said first 0099 All documents and other information sources cited compound is a pyschotherapeutic agent and said second com above are hereby incorporated in their entirety by reference, pound is a Zonisamide. as are Gadde etal, Obesity Res. 9:544-551 (2001) and Gadde 0.112. In the twelfth embodiment, the invention relates to etal, JAMA 289:1820-1825 (2003). the composition of the first embodiment, wherein said first US 2009/00181 15 A1 Jan. 15, 2009

compound is lithium carbonate or lithium citrate and said I0126. In the twenty sixth embodiment, the invention second compound is Zonisamide. relates to the method of the twenty third embodiment, 0113. In the thirteenth embodiment, the invention relates wherein said first compound is administered Subsequent to to the composition of the first embodiment, wherein said first said second compound. compound is valproate and said second compound is Zonisa I0127. In the twenty seventh embodiment, the invention mide. relates to a method of increasing energy expenditure in an 0114. In the fourteenth embodiment, the invention relates individual comprising identifying an individual in need to the composition of the twelfth or thirteenth embodiment, thereof and treating that individual with a first compound and wherein the Zonisamide is in a time-release formulation. a second compound, wherein said first compound is a psy 0115. In the fifteenth embodiment, the invention relates to chotherapeutic agent and said second compound is an anti a method of affecting weight loss, comprising identifying an convulsant. individual in need thereof and treating that individual with a I0128. In the twenty eighth embodiment, the invention psychotherapeutic agent and an anticonvulsant. relates to the method of the twenty seventh embodiment, 0116. In the sixteenth embodiment, the invention relates to wherein said first compound and said second compound are the method of the fifteenth embodiment, wherein said indi administered nearly simultaneously. vidual has a body mass index greater than 25. I0129. In the twenty ninth embodiment, the invention 0117. In the seventeenth embodiment, the invention relates to the method of the twenty seventh embodiment, relates to the method of the fifteenth embodiment, wherein wherein said first compound is administered prior to said the psychotherapeutic agent is selected from the group con second compound. sisting of lithium carbonate, lithium citrate, and Valproate, 0.130. In the thirtieth embodiment, the invention relates to extended release formulations of the above drugs, and com the method of the twenty seventh embodiment, wherein said binations of the above drugs. first compound is administered Subsequent to said second 0118. In the eighteenth embodiment, the invention relates compound. to the method of the fifteenth embodiment, wherein the anti I0131. In the thirty first embodiment, the invention relates convulsant is selected from the group consisting of barbitu to a method of Suppressing the appetite of an individual rates, benzodiazepines, GABA analogues, hydantoins phe comprising identifying an individual in need thereof and nyltriazines, and Succinimides, and pharmaceutically treating that individual with a first compound and a second acceptable salts or prodrugs thereof. compound, wherein said first compound is a psychotherapeu 0119. In the ninteenth embodiment, the invention relates tic agent and said second compound is an anticonvulsant. to the method of the fifteenth embodiment, wherein the anti 0.132. In the thirty second embodiment, the invention convulsant is selected from the group consisting of pentobar relates to the method of the thirty first embodiment, wherein bital, clonazepam, cloraZepate, benzodiazepine, diazepam, said first compound and said second compound are adminis tiagabine, gabapentin, pregabalin, fosphenytoin, phenytoin, tered nearly simultaneously. phenytoin, 5.5-Diphenylhydantoin, carbamazepine, Val I0133. In the thirty third embodiment, the invention relates proate, valproic acid, divalproex, felbamate, levetiracetarn, to the method of the thirty first embodiment, wherein said first carbamazepine, topiramate, oXcarbazepine, Zonisamide, compound is administered prior to said second compound. lamotrigine, methSuximide, ethoSuximide, extended release I0134. In the thirty fourth embodiment, the invention formulations of the above drugs, and combinations of the relates to the method of the thirty first embodiment, wherein above drugs. said first compound is administered Subsequent to said sec 0120 In the twentieth embodiment, the invention relates ond compound. to the method of the fifteenth embodiment, wherein said first I0135) In the thirty fifth embodiment, the invention relates compound and said second compound are administered to a method of affecting weight loss in an individual compris nearly simultaneously. ing identifying an individual in need thereof and treating that 0121. In the twenty first embodiment, the invention relates individual with a combination of lithium carbonate and to the method of the fifteenth embodiment, wherein said first Zonisamide. compound is administered prior to said second compound. 0.136. In the thirty sixth embodiment, the invention relates 0122. In the twenty second embodiment, the invention to a method of affecting weight loss in an individual compris relates to the method of the fifteenth embodiment, wherein ing identifying an individual in need thereof and treating that said first compound is administered Subsequent to said sec individual with a combination of valproate and Zonisamide. ond compound. 0.137 In the thirty seventh embodiment, the invention 0123. In the twenty third embodiment, the invention relates to the method of the thirty fifth or thirty sixth embodi relates to a method of increasing satiety in an individual ments, wherein the individual has a BMI greater than 30. comprising identifying an individual in need thereof and 0.138. In the thirty eighth embodiment, the invention treating that individual with a first compound and a second relates to the method of the thirty fifth or thirty sixth embodi compound, wherein said first compound is a psychotherapeu ments, wherein the individual has a BMI greater than 25. tic agent and said second compound is a anticonvulsant. 0.139. In the thirty ninth embodiment, the invention relates 0.124. In the twenty fourth embodiment, the invention to the method of the thirty fifth or thirty sixth embodiments, relates to the method of the twenty third embodiment, wherein the lithium carbonate or valproate is in a time-release wherein said first compound and said second compound are formulation. administered nearly simultaneously. 0140. In the fortieth embodiment, the invention relates to 0.125. In the twenty fifth embodiment, the invention relates the method of the thirty fifth or thirty sixth embodiments, to the method of the twenty third embodiment, wherein said wherein the plasma concentration level of both the lithium first compound is administered prior to said second com carbonate or valproate and Zonisamide follow a similar con pound. centration profile. US 2009/00181 15 A1 Jan. 15, 2009

0141. In the forty first embodiment, the invention relates to mg, more preferably from about 100 mg to about 400 mg. the method of the thirty ninth embodiment, wherein the However, it may be necessary to use dosages outside these lithium carbonate or valproate and the Zonisamide are admin ranges. istered substantially simultaneously. 0142. In the forty second embodiment, the invention Example 3 relates to the method of the thirty ninth embodiment, wherein the lithium carbonate or valproate is administered prior to the Combination of Zonisamide and Mitrazepine Zonisamide. 0151 Individuals having a BMI of greater than 25 are 0143. In the forty third embodiment, the invention relates identified. Each individual is instructed to take one tablet of to the method of the thirty ninth embodiment, wherein the Zonisamide on a daily basis, in addition to one tablet of lithium carbonate or valproate is administered Subsequent to mitrazepine on a daily basis. Initially, the drugs are adminis the Zonisamide. tered as follows: 8 mg mitrazepine and 64 mg Zonisamide; or 16 mg mitrazepine and 128 mg Zonisamide; or 32 mg EXAMPLES mitrazepine and 252 mg Zonisamide; generally with an mitrazepine/Zonisamide ratio of 1:8. 0144. The examples below are non-limiting and are 0152 The individuals are monitored for a period of merely representative of various aspects of the invention. months. It is recommended that the dosage be adjusted so that each individual loses weight at a rate of 10% of initial weight Example 1 every 6 months. However, the rate of weigh loss for each Use of Zonisamide Alone individual may be adjusted by the treating physician based on the individual’s particular needs. 0145 Individuals taking an antidepressant, or about to 0153. If the initial dosages are not effective, they can be take an antidepressant, who have gained weight as the result increased. of the use of the antidepressant, or are Susceptible to gain weight as the result of the use of the antidepressant, are Example 4 identified. Each individual is instructed to take one 25 mg tablet of Zonisamide on a daily basis, in addition to the anti Combination of Zonisamide and Paroxetine depressant therapy. 0154 Individuals having a BMI of greater than 25 are 0146 The individuals are monitored for a period of identified. Each individual is instructed to take one tablet of months. It is recommended that the dosage be adjusted so that Zonisamide on a daily basis, in addition to one tablet of each individual loses weight at a rate of 10% of initial weight paroxetine on a daily basis. Initially, the drugs are adminis every 6 months. However, the rate of weigh loss for each tered as follows: 10 mg paroxetine and 60 mg Zonisamide; or individual may be adjusted by the treating physician based on 20 mg paroxetine and 120 mg Zonisamide; or 30 mg paroX the individual's particular needs. etine and 180 mg Zonisamide; or 40 mg paroxetine and 240 0147 The dosage of Zonisamide can be from about 25 mg mg Zonisamide; generally with an paroxetine/Zonisamide to about 800 mg per day, generally given once per day or ratio of 1:6. divided (e.g., equally) into multiple doses. Preferably, the 0155 The individuals are monitored for a period of dose is from about 100 mg to about 600 mg per day, more months. It is recommended that the dosage be adjusted so that preferably, the dose is from about 200 mg to about 400 mg per each individual loses weight at a rate of 10% of initial weight day. However, it may be necessary to use dosages outside every 6 months. However, the rate of weigh loss for each these ranges. Zonisamide tablets are usually made and mar individual may be adjusted by the treating physician based on keted in 25 mg, 50 mg, and 100 mg doses. Individual tablets, the individual’s particular needs. or combination of tablets can be used to achieve the desired 0156 If the initial dosages are not effective, they can be dosing. increased. Example 2 Example 5 Use of Topiramate Alone Combination of Zonisamide and Lithium Carbonate 0148 Individuals taking an antidepressant, or about to 015.7 Individuals having a BMI of greater than 25 are take an antidepressant, who have gained weight as the result identified. Each individual is instructed to take one 25 mg of the use of the antidepressant, or are Susceptible to gain tablet of Zonisamide on a daily basis, in addition to one 300 weight as the result of the use of the antidepressant, are mg tablet of lithium carbonate on a daily basis. identified. Each individual is instructed to take one 25 mg 0158. The individuals are monitored for a period of tablet of topiramate on a daily basis, in addition to the anti months. It is recommended that the dosage be adjusted so that depressant therapy. each individual loses weight at a rate of 10% of initial weight 014.9 The individuals are monitored for a period of every 6 months. However, the rate of weigh loss for each months. It is recommended that the dosage be adjusted so that individual may be adjusted by the treating physician based on each individual loses weight at a rate of 10% of initial weight the individual’s particular needs. every 6 months. However, the rate of weigh loss for each 0159. If the initial dosage is not effective, then the Zonisa individual may be adjusted by the treating physician based on mide dosage can be increased by approximately 25 mg per the individual's particular needs. day. If the initial dosage results in a more rapid weight loss 0150. The dosage of topiramate can be from about 25 mg than the above rate, the dosage of each of Zonisamide or to about 1600 mg, preferably from about 50 mg to about 600 lithium carbonate can be reduced. US 2009/00181 15 A1 Jan. 15, 2009

0160. In some cases, it is beneficial to administer one dose istered once a day, but valproate gradually enters the blood of Zonisarnide per day in conjunction with two or three or stream throughout the day, or in the course of a 12 hour more doses of lithium carbonate throughout the day. Lithium period. carbonate may also be in a time-release formulation where the dose is administered once a day, but lithium carbonate Example 8 gradually enters the blood stream throughout the day, or in the course of a 12 hour period. Combination of Zonisamide and Valproate 0161 The above procedure can be followed using lithium citrate, or any other pharmaceutically acceptable salt of 0170 Individuals having a BMI of greater than 25 are identified. Each individual is instructed to take one 50 mg lithium, instead of lithium carbonate. tablet of Zonisamide on a daily basis. In addition, each indi vidual is instructed to take one 250 mg tablet of valproate on Example 6 a daily basis. 0171 The individuals are monitored for a period of Combination of Zonisamide and Lithium Carbonate months. It is recommended that the dosage be adjusted so that each individual loses weight at a rate of 10% of initial weight 0162 Individuals having a BMI of greater than 25 are every 6 months. However, the rate of weigh loss for each identified. Each individual is instructed to take one 25 mg individual may be adjusted by the treating physician based on tablet of Zonisamide on a daily basis. In addition, each indi the individual’s particular needs. vidual is instructed to take one 300 mg tablet of lithium 0172. If the initial dosage is not effective, then the val carbonate on a daily basis. proate dosage can be increased by 20 mg intervals up to 3000 0163 The individuals are monitored for a period of mg per day. If the initial dosage results in a more rapid weight months. It is recommended that the dosage be adjusted so that loss than the above rate, the dosage of each of Zonisamide or each individual loses weight at a rate of 10% of initial weight valproate can be reduced. every 6 months. However, the rate of weigh loss for each individual may be adjusted by the treating physician based on Example 9 the individual’s particular needs. It is recommended that serum creatinine be checked periodically. Combination of Zonisamide and Olanzapine 0164. If the initial dosage is not effective, then the lithium 0173 Individuals having a BMI of greater than 25 are carbonate dosage can be increased so as to achieve blood identified. Each individual is instructed to take one tablet of levels of 0.5 to 1.5 meq/l. If the initial dosage results in a more Zonisamide on a daily basis, in addition to one tablet of rapid weight loss than the above rate, the dosage of each of olanzapine on a daily basis. Initially, the drugs are adminis Zonisamide or lithium carbonate can be reduced. tered as follows: 5 mg olanzapine and 60 mg Zonisamide, or 0.165. The above procedure can be followed using lithium 10 mg olanzapine and 120 mg Zonisamide; generally with an citrate, or any other pharmaceutically acceptable salt of olanzapine/Zonisamide ratio of 1:12. lithium, instead of lithium carbonate. 0.174. The individuals are monitored for a period of months. It is recommended that the dosage be adjusted so that Example 7 each individual loses weight at a rate of 10% of initial weight every 6 months. However, the rate of weigh loss for each Combination of Zonisamide and Valproate individual may be adjusted by the treating physician based on the individual’s particular needs. 0166 Individuals having a BMI of greater than 25 are 0.175. If the initial dosages are not effective, they can be identified. Each individual is instructed to take one 50 mg increased. tablet of Zonisamide on a daily basis, in addition to one 500 mg tablet of valproate on a daily basis. Example 10 0167. The individuals are monitored for a period of months. It is recommended that the dosage be adjusted so that Combination of Zonisamide and Risperidone each individual loses weight at a rate of 10% of initial weight 0176 Individuals having a BMI of greater than 25 are every 6 months. However, the rate of weigh loss for each identified. Each individual is instructed to take one tablet of individual may be adjusted by the treating physician based on Zonisamide on a daily basis, in addition tablet of risperidone the individual's particular needs. on a daily basis. Initially, the drugs are administered as fol 0168 If the initial dosage is not effective, then the lows: 0.5 mg risperidone and 30 mg Zonisamide, 1 mg ris Zonisarnide dosage can be increased by approximately 30 mg peridone and 60 mg Zonisamide, or 2 mg risperidone and 120 per day, though not exceeding 600 mg total per day. If the mg Zonisamide; generally with an olanzapine/Zonisamide initial dosage results in a more rapid weight loss than the ratio of 1:60. above rate, the dosage of each of Zonisamide or valproate can 0177. The individuals are monitored for a period of be reduced. months. It is recommended that the dosage be adjusted so that 0169. In some cases, it is beneficial to administer one dose each individual loses weight at a rate of 10% of initial weight of Zonisamide per day in conjunction with two or three or every 6 months. However, the rate of weigh loss for each more doses of valproate throughout the day. Valproate may individual may be adjusted by the treating physician based on also be in a time-release formulation where the dose is admin the individual’s particular needs. US 2009/00181 15 A1 Jan. 15, 2009

0.178 If the initial dosages are not effective, they can be Zonisamide plus bupropion. In this way cohorts of 10 rats increased. receive all possible combinations of the weight loss drug(s) with mirtazapine or setiptiline. Example 11 Zonisamide and/or Bupropion Prevent the Weight Gain Associated with Mirtazapine or Setiptiline Rat numbers and groups Treatment Weight loss agent Vehicle Setiptiline (tbd) Mirtazapine (tbd) Background Vehicle 10 10 10 0179 Mirtazapine shows considerable promise as a Zonisamide (tbd) 10 10 10 Bupropion (tbd) 10 10 10 therapy for sleep apnea, but it causes weight gain in some Zonisamide (tbd) + 10 10 10 patients. This weight gain limits the use of mirtazapine as a Bupropion (tbd) therapy for sleep apnea or as an antidepressant. Addition of Zonisamide, or bupropion, or Zonisamide plus bupropion, to concomitant mirtazapine treatment decreases the weight gain associated with mirtazapine, in a rodent model of mirtazap Electrophysiology ine-induced weight gain. 0185. The electrophysiological response of POMC neu 0180. The melanocortin system controls energy balance. rons to mirtazapine and to setiptiline is determined. It is then Mirtazapine and Setiptiline change the activity of melanocor determined if co-treatment with Zonisamide, or bupropion, or tin circuits. Zonisamide, or bupropion, or Zonisamide plus Zonisamide plus bupropion prevents the expected decrease in bupropion reverse this change in neuronal activity. POMC activity due to mirtazapine or setiptiline. 0181. The melanocortin system consists of Proopiomel 0186 Preliminary data show that sub-threshold doses of anocortin (POMC) neurons, the cognate melanocortin recep Zonisamide and bupropion synergistically inhibit acute food tors (MC4R) and the agouti-related peptide neurons in the intake in mice, which is further evidence of powerful synergy arcuate nucleus of the hypothalamus. It is well established in between Zonisamide and bupropion to inhibit food intake in humans and animals that the melanocortin system controls mice after a 16 hr fast. energy balance and the most common genetic cause of obe 0187. In other preclinical experiments it has been shown sity in humans is congenital lack of MC4R. that Zonisamide and bupropion each inhibit food intake. 0182. It has recently been shown that many compounds These effects had faded by 4 hours, but the combination was that influence energy balance modify the activity of melano effective when each compound alone was ineffective. The cortin circuits. In particular, it has been shown that bupropion weight reducing effects of Zonisamide and bupropion have and Zonisamide increase the electrophysiological activity of also been well demonstrated in humans (Gadde et al., 2003: POMC neurons. As part of this research some of the receptors Gadde et al., 2001). that can regulate the activity of POMC neurons have been 0188 It has also been shown that Zonisamide in combina identified; specifically it has been shown that 5-HT2C and tion with bupropion strongly increases the electrophysiologi 5-HT1B receptors increase the activity of POMC neurons as cal activity of POMC neurons in brain slices from POMC does dopamine D2 R. The clear role of 5-HT2CR in regulat EGFP mice. It has been shown that a large increase in rate of ing the activity of POMC neurons suggests that compounds spontaneous action potentials in POMC neurons would be like mirtazapine, which is an antagonist at this receptor, expected to stimulate significant secretion of C-MSH from modify energy balance to induce an anabolic state, favoring POMC neurons, and consequent activation of MC4 R to Weight gain. inhibit food intake and decrease body weight gain. In vivo Pharmacology Procedures 0183) We have developed a model to pre-clinically test the In vivo Pharmacology effects of mirtazapine on body weight gain. Dose-ranging studies are performed to determine the dose that best demon 0189 Female Sprague-Dawley rats weighing about 300 strates the weight gain caused by mirtazapine or by Setiptiline grams at the start of the experiment are used. Under isoflurane in the "rat-weight gain assay'. Zonisamide, or bupropion, or anesthesia, Alzet osmotic minipumps (2ml2) are implanted Zonisamide plus bupropion are tested to decrease the weight subcutaneously between the shoulder blades. The rats are gain seen in response to concomitant mirtazapine or setip returned to their home cages after recovery. The minipumps tiline therapy. Initially, a dose of 30 mg/kg of Zonisamide deliver 5 uL per hour for 14 days. A range of doses of mir (bid) is used, but the dose in the experiment ranges from 20 tazapine (from 0.1 to 20mg/kg/day dissolved in DMSO/sa mg/kg to 90 mg/kg (bid). Bupropion is used initially at a dose line) are used. Animals are housed individually and Supplied of 190 mg/kg/day, the dose in the experiment ranges from with standard laboratory chow. Food consumed and animal 50-190 mg/kg/day. Mirtazapine or setiptiline are used as solu weights are recorded every 3 days, to minimize disruption of tions in minipumps. The concentration of the solution ranges the animals. between 0.1 uM to 10 mM. In some experiments, the concen 0190. We have already shown in mice that bupropion, tration is calculated to provide a dose of about 1 mg/kg/day. In Zonisamide, and Zonisarnide plus bupropion have pro certain experiments, the concentration is 10 uM. nounced effects on food intake after intra-peritoneal injec 0184. In a 4x3 design rats receive implants that secrete tion. We will develop chronic infusion methods to test the mirtazapine, or setliptiline, or vehicle. Some rats also receive effects of bupropion, or Zonisamide and Zonisamide plus co-treatment with Saline, some receive Zonisamide, some bupropion on weight gain over 14 days using the following receive bupropion, and others receive co-treatment with groups: US 2009/00181 15 A1 Jan. 15, 2009

0191 7 groups of 6 rats (6 doses of mirtazapine (0.1, 0.5, which is an antagonist at both these receptors, modify energy 1, 5, 10, 20 mg/kg), +Saline) balance to induce an anabolic State, favoring weight gain. 0.192 The doses of Zonisamide, and bupropion, and Zonisarnide plus bupropion that cause weight loss in this rat Study Design model in the preliminary studies are determined; the co In vivo Pharmacology treatment experiments (mirtazapine plus Zonisamide plus 0.197 Rats receive implants that secrete olanzapine (or bupropion) are then performed. vehicle in control groups). Some also receive co-treatment with Zonisamide; others get co-treatment with Zonisamide Electrophysiology plus bupropion. Initially, a dose of 30 mg/kg of Zonisamide (bid) is used, but the dose in the experiment ranges from 20 0193 The electrophysiological activity of Proopiomel mg/kg to 90 mg/kg (bid). Bupropion is used initially at a dose anocortin (POMC) neurons in brain slices from POMC of 190 mg/kg/day, the dose in the experiment ranges from EGFP mice are recorded. The POMC neurons in these mice 50-190 mg/kg/day. Olanzapine is used as a solution in are identified by the expression of green fluorescent protein minipumps. The concentration of the solution ranges between (EGFP) in these, and only these, cells. The frequency of 0.1 uM to 10 mM. In some experiments, the concentration is action potentials in these neurons are recorded using standard calculated to provide a dose of about 1.75 mg/kg/day. In electrophysiological techniques. In particular loose cell certain experiments, the concentration is 10 uM. attached patch configuration is used to determine action potential frequency, whilst minimally disturbing the cells. 0194 It has been shown that Zonisamide, or bupropion, or Rat numbers and groups Zonisamide plus bupropion increase the activity of POMC neurons. The basal activity is recorded, and then mirtazapine Weight loss agent Vehicle Olanzapine (1.75 mg/day) or setiptiline is added to the tissue bath to determine the effect Vehicle 10 10 Zonisamide (tbd) 10 10 of the antidepressant on the activity of POMC neurons. If Zonisamide (tbd) + 10 10 mirtazapine or setiptiline inhibits the activity of POMC neu bupropion (tbd) rons, the increase in neuronal activity by treating the brain slices with bupropion, or Zonisamide or Zonisamide plus (0198 Preliminary data on the effect of Zonisamide com bupropion is tested. bined with bupropion on electrophysiological activity of POMC neurons in brain slices from POMC-EGFP mice show Example 11 the increase in rate of spontaneous action potentials in POMC neurons. This large increase stimulates significant secretion Zonisamide Plus Bupropion Prevent the Weight Gain of C-MSH from POMC neurons, and consequently activates Associated with Olanzapine Treatment MC4 R to inhibit food intake and decrease body weight ga1n. Background Procedures 0.195. In this experiment, the effect of co-treatment with In vivo Pharmacology drug combinations on the weight gain associated with olan Zapine use is tested. Specifically, addition of Zonisamide or 0199 Female Sprague-Dawley rats weighing about 300 Zonisamide plus bupropion to concomitant olanzapine treat grams at the start of the experiment are used. Under isoflurane anesthesia, Alzet osmotic minipumps (2ml2) are implanted ment is shown to decrease the weight gain associated with subcutaneously, between the shoulder blades. The rats are olanzapine, in a validated rodent model of olanzapine-in returned to their home cages after recovery. The minipumps duced weight gain. deliver 5uL per hour for 14 days. Olanzapine is dissolved in 0196. The melanocortin system consists of Proopiomel dH2O+10% dilute lactic acid. A pH of about 3.5 enables the anocortin (POMC) neurons, the cognate melanocortin recep olanzapine to dissolve completely and produce a golden solu tors (MC4R) and the agouti-related peptide neurons in the tion. This pH level has no effect on the animals in either the arcuate nucleus of the hypothalamus. It is well established in drug groups or the vehicle group. The animals are housed humans and animals that the melanocortin system controls individually and are supplied with standard laboratory chow. energy balance, and the most common genetic cause of obe Food consumed and animal weights are recorded every 3 sity in humans is congenital lack of MC4 R. It has recently days, to minimize disruption of the animals. been shown that many compounds that influence energy bal 0200. It has been shown in mice that Zonisamide and ance modify the activity of melanocortin circuits. In particu Zonisamide plus bupropion have pronounced effects on food lar, it has been shown that bupropion and Zonisamide increase intake over 24 hrs after intra-peritoneal injection. Similar the electrophysiological activity of POMC neurons. It has mini-pump based methods are developed to test the effects of also been shown that cannabinoid antagonists activate this Zonisamide and Zonisamide plus bupropion on weight gain same circuitry. We have identified some of the receptors that over 14 days using the following groups: can regulate the activity of POMC neurons; in particular we 0201 7 groups of 6 rats (6 doses of Zonisamide, +saline) have shown that 5-HT2C and 5-HT1B receptors increase the 0202 7 groups of 6 rats (6 doses of bupropion, +saline) activity of POMC neurons as does dopamine D2 R. The clear 0203 The doses of Zonisamide and bupropion that cause role of D2 R and 5-HT2CR in regulating the activity of weight loss in this rat model are determined in Smaller pre POMC neurons shows that compounds like olanzapine, liminary studies. The co-treatment experiments (olanzapine US 2009/00181 15 A1 Jan. 15, 2009 plus Zonisamide plus bupropion) are then performed. Total mg/day, the patient reported feeling hyperactive; hence, the animals tested are: 60+42+42=144 rats. The experiments are dose was reduced back to 150 mg/day. After 6 months, the run three times to confirm the results. patient lost 23.6 lbs. However, while continuing to receive bupropion, the patient regained 10.6 lbs over the next 10 Electrophysiology months. At this point, Zonisamide was added to her medica 0204 The electrophysiological activity of Proopiomel tion regimen at 100 mg/day and the dose was increased to 200 anocortin (POMC) neurons in brain slices from POMC mg/day after two weeks. The patient lost 15 lbs over the next EGFP mice are recorded. The POMC neurons in these mice 4 months and reported no adverse effects. She remained free are identified by the expression of green fluorescent protein of bipolar disorder symptoms. (EGFP) in these, and only these, cells. The frequency of 0209. The case illustrates two advantages of the combina action potentials in these neurons are recorded using standard tion therapy of bupropion and Zonisamide. 1) Although electrophysiological techniques. In particular, loose cell bupropion helped in decreasing weight gain resulting from attached patch configuration is used to determine action olanzapine and valproate, the patient could not take a higher potential frequency, whilst minimally disturbing the cells. dose (300-400 mg/day) of bupropion because of precipitation 0205. It has been shown that Zonisamide and Zonisamide of hypomanic symptoms. The risk of induction of manic or plus bupropion increase the activity of POMC neurons. The hypomanic symptoms with use of antidepressant medications basal activity is recorded, and then olanzapine is added to the in Susceptible patients is well documented. 2) Zonisamide tissue bath to determine the effect of olanzapine on the activ helped in further offsetting weight gain associated with olan ity of POMC neurons. Pharmacological data show that olan Zapine and valproate after the patient lost weight initially with Zapine decreases the activity of POMC neurons. Then the bupropion and regained some of weight lost. increase in neuronal activity is tested again by treating the What is claimed is: brain slices with Zonisamide or Zonisamide plus bupropion. 1. A pharmaceutical composition for the prevention of weight gain associated with the use of a psychotherapeutic Example 12 agent comprising a first compound and a second compound, wherein said first compound is a psychotherapeutic agent and Case Study of Combination of Zonisamide, Lam said second compound is an anticonvulsant. otrogine, and Clonazepam 2. The pharmaceutical composition of claim 1, wherein 0206. A 49 year-old woman having biopolar disorder, said psychotherapeutic agent is selected from the group con Type I, had been treated for just over year by her psychiatrist sisting of lithium carbonate, lithium citrate, Valproate, mix using clonazepam 1 mg qHS, fluoxetine 20 mg qd, and lam tures thereof, and pharmaceutically acceptable salts or pro otrogine 300 mg qD. One particular complaint was that she drugs thereof. had “constant thoughts of eating. Her psychiatrist started her 3. The pharmaceutical composition of claim 1, wherein on Zonisamide 100 mg ql). She reported that the Zonisamide said anticonvulsant is selected from the group consisting of significantly reduced her craving for food and prevented topiramate, Zonisamide, and pharmaceutically acceptable weight gain. The dose was continued and despite multiple salts or prodrugs thereof, and combinations thereof. stressors at home, she continued to do well on the treatment 4. The pharmaceutical composition of claim 1, wherein regimen. said first compound is a pyschotherapeutic agent and said second compound is a Zonisamide. Example 13 5. The pharmaceutical composition of claim 4, wherein said first compound is lithium carbonate or lithium citrate. Case Study of Combination of Zonisamide, Paroxet 6. The pharmaceutical composition of claim 4, wherein ine and Risperidone said first compound is valproate. 0207. A 45 year old female patient with social phobia and 7. The pharmaceutical composition of claim 1, wherein Schizoaffective disorder was treated with paroxetine aug said first compound is a salt of lithium and said second com mented with risperidone. She had marked increase inappetite pound is Zonisamide. and gained 40 pounds. A trial of bupropion alone did not 8. The pharmaceutical composition of claim 1, wherein cause significant weight loss. She was therefore started on said first compound is valproic acid, or a pharmaceutically Zonisamide 100 mg, incraesed to 200mg. In 3 weeks she lost acceptable salt, ester, amide, or prodrug thereof, and said 12 pounds. The dose was then increased to 300 mg and then second compound is Zonisamide. to 600 mg. In 5 months her weight returned to baseline. The 9. The pharmaceutical composition of claim 1, wherein psychiatric symptoms also improved. said first compound is mirtazapine and said second com pound is Zonisamide. Example 14 10. The pharmaceutical composition of claim 1, wherein said first compound is mirtazapine and said second com Case Study of Combination of Zonisamide, Olanzap pound is bupropion. ine, Valproate, and Bupropion 11. The pharmaceutical composition of claim 1, wherein 0208. A 30 year-old female patient with a diagnosis of said first compound is setliptiline and said second compound bipolar disorder gained 56 lbs while receivingolanzapine and is Zonisamide. valproate over 5 years. Despite significant weight gain, as her 12. The pharmaceutical composition of claim 1, wherein mental illness was effectively controlled, these medications said first compound is setliptiline and said second compound were continued. She was clinically obese with a BMI of 33.8 is bupropion. kg/m. In an effort to assist in weight reduction, bupropion 13. The pharmaceutical composition of claim 1, wherein was added at 150 mg/day while olanzapine and valproate said first compound is mirtazapine and said second com were continued. When bupropion dose was raised to 300 pound is a combination of Zonisamide and bupropion. US 2009/00181 15 A1 Jan. 15, 2009

14. The pharmaceutical composition of claim 1, wherein 18. A method of Suppressing the appetite of an individual said first compound is setiptiline and said second compound comprising identifying an individual in need thereof and is a combination of Zonisamide and bupropion. treating that individual with a first compound and a second 15. A method of preventing weight loss associated with the compound, wherein said first compound is a psychotherapeu use of a psychotherapeutic agent, comprising identifying an tic agent and said second compound is an anticonvulsant. individual in need thereof and treating that individual with a 19. The method of claim 18, wherein the psychotherapeu psychotherapeutic agent and an anticonvulsant. tic agent is selected from the group consisting of lithium 16. The method of claim 15, wherein the psychotherapeu carbonate, lithium citrate, and valproate, and pharmaceuti tic agent is selected from the group consisting of lithium cally acceptable salts, esters, amides, or prodrugs thereof, and carbonate, lithium citrate, and valproate, and pharmaceuti said anticonvulsant is Zonisamide. cally acceptable salts, esters, amides, or prodrugs thereof, and 20. The method of claim 18, wherein the psychotherapeu said anticonvulsant is Zonisamide. tic agent is selected from the group consisting of mirtazapine, 17. The method of claim 15, wherein the psychotherapeu and Setiptiline, and pharmaceutically acceptable salts, esters, tic agent is selected from the group consisting of mirtazapine, amides, or prodrugs thereof, and said anticonvulsant is and Setiptiline, and pharmaceutically acceptable salts, esters, Zonisamide. amides, or prodrugs thereof, and said anticonvulsant is Zonisamide.