US 20130.045979A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0045979 A1 Sanfilippo (43) Pub. Date: Feb. 21, 2013

(54) METHOD OF TREATING MAJOR Publication Classification DEPRESSIVE DSORDER (51) Int. Cl. (75) Inventor: Louis Sanfilippo, New Haven, CT (US) A613 L/65 (2006.01) A613 L/496 (2006.01) A613 L/53 (2006.01) (73) Assignee: LCS GROUP, LLC, New Haven, CT A6IP 25/24 (2006.01) (US) (52) U.S. Cl...... 514/242: 514/626; 514/253.04 (57) ABSTRACT The invention provides methods of treating depressive disor (21) Appl. No.: 13/585.426 ders, in particular major depression but other depressive orders also, with prodrug stimulants or analogs including amphetamine prodrugs, methylphenidate prodrugs, and (22) Filed: Aug. 14, 2012 methylphenidate analogs. Such methods of treatment may utilize the prodrug stimulant or analog as monotherapy or, more commonly, as an adjunct to antidepressant medication Related U.S. Application Data treatment to augment their effect. The invention includes combination methods of treatment in which an amphetamine (63) Continuation of application No. 12/646,441, filed on prodrug, methylphenidate prodrug, or methylphenidate ana Dec. 23, 2009, now abandoned, which is a continua- log is administered to an individual in need with one or more tion of application No. 12/666.460, filed on Oct. 6, other active agents, either in separate forms or as a single 2010, now Pat. No. 8,318,813, filed as application No. pharmaceutical formulation. Packaged pharmaceutical com PCT/US2008/001002 on Jan. 24, 2008. positions containing an amphetamine or methylphenidate s prodrug, instructions for using the prodrug to treat certain (60) Provisional application No. 60/972,046, filed on Sep. disorders, and optionally one or more other active agents are 13, 2007. provided by the invention. US 2013/0045979 A1 Feb. 21, 2013

METHOD OF TREATING MAJOR behaviors and weight gain may be a direct effect of Such DEPRESSIVE DSORDER medication(s). Psychotropic medications may also exacer bate an underlying binge eating disorder in Some patients. FIELD OF INVENTION 0006 Medical complications associated with binge eating disorder include high blood pressure, high cholesterol and 0001. The inventor has discovered that amphetamine pro triglycerides, kidney disease (and failure), gallbladder dis drugs and methylphenidate prodrugs are useful for treating a ease, arthritis, bone deterioration, stroke, upper respiratory number of central nervous system disorders. Methods of infections, skin disorders, menstrual irregularities, ovarian treating binge eating disorders, obesity resulting from binge abnormalities, and pregnancy complications. Psychiatric eating behavior, and depression are included herein. The problems associated with, or exacerbated by, binge eating invention includes methods of treating certain co-morbidities disorder include depressive disorders, mood disorders, anxi in ADHD (Attention-Deficit Hyperactivity Disorder) and ety disorders, ADHD and ADD, personality disorders, other ADD patients; for example the invention includes methods of eating disorders, Suicidal thoughts, and Substance abuse dis treating generalized anxiety disorder, obsessional and rumi orders. native thought disorders, and obsessive/compulsive behavior 0007 Individuals with binge eating disorder may respond in ADHD and ADD patients. Methods of treatment include to treatment with antidepressants, though Such medications methods in which the amphetamine prodrug, methylpheni may contribute to a worsening of binge eating symptoms, date prodrug, or methylphenidate analog is the only active along with weight gain, either at the outset of treatment or agent. The invention also includes combination methods of over time. treatment in which an amphetamine prodrug, methylpheni 0008 2. Depression date prodrug, or methylphenidate analog is administered with 0009. Depression is often difficult to treat, as some one or more other active agents. Methods of use described patients fail to respond to an initial pharmacologic interven herein include informing a user that an amphetamine prodrug, tion and a decision must be made to Switch agents, augment methylphenidate prodrug, or methylphenidate analog may be with another medication(s), or combine multiple pharmaco used to treat any of the disorders listed above. The invention logic agents. Combining medications, while often helpful, includes pharmaceutical compositions comprising an can sometimes be problematic with added side effect bur amphetamine prodrug, methylphenidate prodrug, or meth dens. Side effects of certain psychotropic medication some ylphenidate analog together with one or more other active times used to offer adjunct treatment to patients already tak agents in a single dosage form. Packaged pharmaceutical ing antidepressants may include weight gain and obesity. compositions containing an amphetamine prodrug, meth 0010 Individuals treated for major depressive disorders ylphenidate prodrug, or methylphenidate analog with instruc may show a positive response or full remission of symptoms tions for using the composition to treat one of the disorders to medication treatment, though recent clinical evidence Sug listed above are also provided. gests remission rates following an adequate course of mono therapy treatment may as low as 30-40%. Further, clinical BACKGROUND studies suggest an unusually large percentage of depressed 0002 1. Binge Eating Disorder and Obesity Resulting individuals treated with antidepressant medication, greater from Binge Eating Disorder than 30-40% in various clinical studies, show only a partial 0003 Binge Eating Disorder is a form of Eating Disorder response (for example, full remission is not achieved but there Not Otherwise Specified according the Diagnostic and Sta is some measure of improvement in depressive symptoms). tistical Manual of Mental Disorders (DSM-IV-TR). As Some patients may be refractory or resistant to treatment defined by the DSM-IV-TR, it is characterized by recurrent and fail to respond to one, or in Some cases, multiple mono binge eating episodes. therapy and combination antidepressant medication treat 0004 Commonly described symptoms of binge eating mentS. disorder include frequent dieting and weight loss, hoarding of 0011 Major depressive disorders similarly may lead to food, hiding empty food containers, eating late at night, attri deteriorating physical health and may increase the risk of bution of one's successes and failures to weight, avoiding morbidity and mortality in patients with concurrent medical Social situations where food may be present, and feeling conditions. depressed or anxious. Binge eating also may cause rapid and 0012 Similarly, depressive disorders are often associated unhealthy weight gain (or loss), weight fluctuations, and with, or may exacerbate, other mood disorders, anxiety dis chronic erratic eating behavior. Binge eating disorder and orders, attention deficit hyperactivity disorder (ADHD or symptoms associated with binge eating disorder may result in ADD), psychotic disorders, personality disorders, eating dis obesity though obesity is not necessarily a result of binge orders, cognition and cognitive disorders, Substance abuse eating disorder. Further, patients with binge eating disorder disorders, and Suicidal ideation. are often not obese and may even have a below normal 0013 There exists an unmet and important clinical need weight. for treatments for binge eating disorders, obesity resulting 0005. The biological basis of binge eating disorder is from binge eating behavior, and depression that is only par poorly understood. Binge eating disorder is difficult to treat tially responsive to medication and intractable (e.g. treat and carries significant medical and psychiatric risks. Pharma ment-resistant) depression. The present invention fulfills this cologic interventions have been of limited Success and some need and provides additional advantages described herein. times cause a worsening of binge eating symptoms. A number of psychotropic medications, including but not limited to SUMMARY OF THE INVENTION antidepressants, antipsychotics, antimanic agents, and mood 0014. The inventor has discovered that amphetamine pro modulating medications are known to cause binge eating, drugs, including lisdexamfetamine dimesylate, methylpheni dysregulation of appetite, and weight gain. Binge eating date prodrugs, and certain methylphenidate analogs, are use US 2013/0045979 A1 Feb. 21, 2013

ful for treating binge eating disorders, obesity resulting from 0020. The invention includes articles of manufacture com binge eating behavior, and depression. Furthermore amphet prising an amphetamine prodrug, methylphenidate prodrug, amine prodrugs, methylphenidate prodrugs, and certain or methylphenidate analog in a container and printed label methylphenidate analogs have been found useful for treating ing. The printed labeling states that the amphetamine pro certain co-morbidities in ADHD and ADD patients. The drug, methylphenidate prodrug, or methylphenidate analog is invention includes methods of treating generalized anxiety useful for treating a binge eating disorder, obesity resulting disorder, obsessional and ruminative thought disorders, and from binge eating behavior, or depression. In other embodi obsessive/compulsive behavior in patients, particularly in ments the printed labeling states that the amphetamine pro ADHD/ADD patients. Methods of using amphetamine pro drug, methylphenidate prodrug, methylphenidate analog is drugs, methylphenidate prodrugs, or methylphenidate ana useful for treating generalized anxiety disorder, obsessional logs, as a monotherapy for treating these conditions and dis and ruminative thought disorders, and obsessive/compulsive orders or in combination with one or more other active agents behavior in a patient, particularly in a patient having ADHD are provided herein. or ADD. 0015 The invention includes a method of treating binge eating disorder or obesity resulting from binge eating behav DETAILED DESCRIPTION ior, comprising diagnosing a patient as having a binge eating disorder or obesity resulting from binge eating behavior and Terminology providing an effective amount of amphetamine prodrug, 0021 Prior to setting forth the invention in detail, it may be methylphenidate prodrug, or methylphenidate analog to the helpful to provide definitions of certain terms to be used patient. herein. Compounds of the present invention are described 0016. The invention also includes a method of treating using standard nomenclature. Unless defined otherwise, all depression comprising diagnosing a patient as having depres technical and Scientific terms used herein have the same sion and providing an effective amount of amphetamine pro meaning as is commonly understood by one of skill in the art drug, methylphenidate prodrug, methylphenidate analog to to which this invention belongs. the patient. 0022. The terms “a” and “an do not denote a limitation of 0017. The invention further provides a method of treating quantity, but rather denote the presence of at least one of the generalized anxiety disorder, obsessional and ruminative referenced item. thought disorders, or obsessive/compulsive behavior in a 0023. An “active agent’ means any compound, element, patient having ADHD or ADD or other patient. In an ADHD or mixture that when administered to a patient alone or in or ADD patient this method comprises diagnosing a patient combination with another agent confers, directly or indi having ADHD or ADD and as also having at least one of rectly, a physiological effect on the patient. When the active generalized anxiety disorder, obsessional and ruminative agent is a compound, salts, Solvates (including hydrates) of thought disorders, or obsessive/compulsive behavior, and the free compound or salt, crystalline and non-crystalline providing an effective amount of amphetamine prodrug, forms, as well as various polymorphs of the compound are methylphenidate prodrug, or methylphenidate analog to the included. Compounds may contain one or more asymmetric patient. elements such as stereogenic centers, Stereogenic axes and 0018. In each of these methods the amphetamine prodrug, the like, e.g. asymmetric carbonatoms, so that the compounds methylphenidate prodrug, or methylphenidate analog may be can existin different Stereoisomeric forms. These compounds provided as the only active agent, i.e. as a monotherapy, or can be, for example, racemates or optically active forms. For may be provided together with one or more other active compounds with two or more asymmetric elements, these agents, i.e. as a combination, adjunct, or augmentation compounds can additionally be mixtures of diastereomers. therapy. For compounds having asymmetric centers, it should be 0019. In a separate embodiment, the invention includes a understood that all of the optical isomers in pure form and method of using an amphetamine prodrug, methylphenidate mixtures thereof are encompassed. In addition, compounds prodrug, or methylphenidate analog comprising informing a with carbon-carbon double bonds may occur in Z- and user that the amphetamine prodrug, methylphenidate pro E-forms, with all isomeric forms of the compounds being drug, methylphenidate analog may be used to treat binge included in the present invention. In these situations, the eating disorder or obesity resulting from binge eating behav single enantiomers, i.e., optically active forms can be ior. The invention also includes a method of using an amphet obtained by asymmetric synthesis, synthesis from optically amine prodrug, methylphenidate prodrug, or methylpheni pure precursors, or by resolution of the racemates. Resolution date analog comprising informing a user that the of the racemates can also be accomplished, for example, by amphetamine prodrug, methylphenidate prodrug, or meth conventional methods such as crystallization in the presence ylphenidate analog may be used to treat depression. The of a resolving agent, or chromatography, using, for example a invention further includes a method of using an amphetamine chiral HPLC column. A "dosage form' means any unit of prodrug, methylphenidate prodrug, or methylphenidate ana administration of an active agent. log comprising informing a user that the amphetamine pro 0024 “Binge eating disorder is a form of Eating Disorder drug, methylphenidate prodrug, methylphenidate analog may Not Otherwise Specified. As defined by the DSM-IV-TR, it is be used to treat certain co-morbidities in ADHD and ADD characterized by recurrent binge eating episodes. Such epi patients, or may be used to treat certain CNS disorders in sodes include eating larger amounts of food than normal patients not diagnosed with ADHD or ADD, including gen during a short period of time (for instance, within a two hour eralized anxiety disorder, obsessional and ruminative thought period) and a lack of control over eating during the binge disorders, and obsessive/compulsive behavior. The invention episode (for instance, one cannot stop eating). According to includes (i) lisdexamfetamine dimeSylate and (ii) one or more the DSM-IV-TR, binge eating disorders are associated with other active agent(s) combined in a single dosage form. three or more of the following symptoms: eating until uncom US 2013/0045979 A1 Feb. 21, 2013 fortably full; eating large amounts of food when not physi Co), or The Montgomery-Asperg Depression Rating Scale cally hungry: eating much more rapidly than normal; eating (MADRS). Such ratings scales may involve patient self-re alone on account of embarrassment over how much one is port or be clinician rated. A 50% or greater reduction in a eating; and feeling disgusted, depressed or guilty after over depression ratings Scale score over the course of a clinical eating. Additionally, individuals with binge eating disorder trial (starting point to endpoint) is typically considered a feel distress about their binging behavior. The DSM-IV-TR favorable response for most depression symptoms rating also characterizes binge eating to occur, on average, at least 2 scales. “Remission' in clinical studies of depression often days a week for six months, while not being associated with refers to achieving at, or below, a particular numerical rating the regular use of inappropriate compensatory behaviors such score on a depression symptoms rating scale (for instance, as purging or excessive exercise and not occurring exclu less than or equal to 7 on the HRSD7; or less than or equal to sively during the course of bulimia nervosa or anorexia ner 5 on the QIDS-SR: or less than or equal to 10 on the Vosa. As used herein "depression' includes major depressive MADRS). disorder, dysthymic disorder, depressive disorder not other 0029 Binge eating behavior may be assessed by different wise specified (for instance, premenstrual dysphoric disor methods though is commonly determined by the frequency of der), and depressive episodes that may be present in another binge eating episodes occurring over a specific period of time disorder (e.g. as in other mood disorders such as bipolar (i.e., the number of binges per week; or the mean number of disorder or a mood disorder due to a general medical condi binges over two week periods). Another form of assessment tion). may quantify the number of “binge-days', that is, the number 0025 Depressive disorders represent one of four classes of of days in which the patient has binged in any form (i.e., mood disorders listed in the DSM-IV-TR, the other major whether once or multiple times) and determining the fre forms of mood disorders include bipolar disorders, mood quency of binge-days over a specific time frame. disorders due to a general medical condition, and Substance 0030) “Generalized Anxiety Disorder” as defined by the induced mood disorders, all of which may demonstrate symp DSM IV-TR, and as the term is used herein, is a disorder toms of depression or low mood. Major depressive episodes meeting the following criteria: A. At least 6 months of “exces may be present in a depressive disorder, which according to sive anxiety and worry about a variety of events and situa the DSM-IV-TR include major depressive disorder, dysthy tions. Generally, “excessive' can be interpreted as more than mic disorder, and depressive disorder not otherwise specified would be expected for a particular situation or event. Most (for instance, premenstrual dysphoric disorder). people become anxious over certain things, but the intensity 0026 Depressive symptoms or features such as low mood, of the anxiety typically manifests in the following manner: diminished interest in activities, psychomotor slowing oragi 0031 A. There is significant difficulty in controlling the tation, changes in appetite, poor concentration or indecisive anxiety and worry. ness, excessive guilt or feelings of worthlessness, and Suicidal 0032 B. The presence for most days over the previous six ideations may occur in the context of depressive disorders, months of 3 or more (only 1 for children) of the following bipolar disorders, mood disorders due to a general medical symptoms: 1. Feeling wound-up, tense, or restless, 2. Easily condition, Substance-induced mood disorders, other unspeci becoming fatigued or worn-out, 3. Concentration problems, fied mood disorders, and also may be present in association 4. Irritability, 5. Significant tension in muscles, and 6. Diffi with a range of other psychiatric disorders, including but not culty with sleep. limited to psychotic disorders, cognitive disorders, eating 0033 C. The symptoms are not part of another mental disorders, anxiety disorders and personality disorders. The disorder. longitudinal course of the disorder, the history and type of 0034. D. The symptoms cause “clinically significant dis symptoms, and etiologic factors help distinguish the various tress” or problems functioning in daily life. “Clinically sig forms of mood disorders from each other. nificant is the part that relies on the perspective of the treat 0027. A “major depressive episode, according to the ment provider. Some people can have many of the DSM-IV-TR, involves five or more of the following symp aforementioned symptoms and cope with them well enough toms in the same 2 week period, signifying a change from to maintain a high level of functioning. previous functioning, of which one symptom is either 1) 0035 E. The condition is not due to a substance or medical depressed mood or 2) a loss of interest or pleasure. The other issue. The severity of Generalized Anxiety Disorder may be symptoms include weight loss or weight gain, insomnia or assessed using a commonly accepted test for assessing the hypersomnia, psychomotor retardation or agitation, fatigue anxiety severity, such as the Hamilton Anxiety Rating Scale or lethargy, feelings of worthlessness or excessive guilt, poor (HAM-A) or the Generalized Anxiety Disorder Severity concentration, or recurrent thoughts of death or Suicide. Such Scale (GADSS). symptoms cause significant distress or impairment and are 0036 "Obsessive behavior” may arise in many different not due to a general medical or Substance abuse condition. clinical forms, including recurrent thoughts, impulses or 0028 “Depression symptoms rating scale” refers to any images; perseverative thinking patterns; or highly ruminative one of a number of standardized questionnaires, clinical mental behavior. Such symptoms often, but not necessarily, instruments, or symptom inventories utilized to measure occur in the context of obsessive-compulsive disorder. “Com symptoms and symptom severity in depression. Such rating pulsive behavior, sometimes referred to as compulsions, scales are often used in clinical studies to define treatment may similarly take a myriad of clinical forms, from more outcomes, based on changes from the study's entry point(s) to conventional obsessive-compulsive disorder symptoms (i.e., endpoint(s). Such depression symptoms rating scales “checking”, “ordering or "hoarding behaviors) to such include, but are not limited to. The Quick Inventory of symptoms as compulsive gambling and Substance abuse, Depressive-Symptomatology Self-Report (QIDS-SR), the sexual and internet compulsions, and compulsive exercising 17-Item Hamilton Rating Scale of Depression (HRSD7), the or lying. The Yale-Brown Obsessive Compulsive Scale 30-Item Inventory of Depressive Symptomatology (IDS (Y-BOCS) is often used to assess symptom severity for US 2013/0045979 A1 Feb. 21, 2013 patients that have both obsessions and compulsions, with active agent, including information on safety, efficacy, dos scores reflecting symptoms severity (for instance, 0-7 as Sub ing, administration, or pharmacokinetics. Examples of medi clinical through 32-40 as severe). cal workers include physicians, pharmacists, physicians 0037 “Obesity” is defined as a BMI (Body Mass Index) assistants, nurses, caretakers, emergency medical workers, >30 (kg/m). and Veterinarians. 0038 “Efficacy” means the ability of an active agent 0044 Apatient’ means any human or non-human animal administered to a patient to produce a therapeutic benefit in in need of medical treatment. Medical treatment can include the patient. treatment of an existing condition, such as a disease or disor 0039. The terms "amphetamine prodrug and “meth der, prophylactic or preventative treatment, or diagnostic ylphenidate prodrug” refer to any product that contains either treatment. In some embodiments the patient is a human an amphetamine (CAS Reg. No. 300-62-9) or methylpheni patient. date (CAS Reg. No. 113-45-1) compound conjugated to a 0045. As used herein “a pharmaceutical supplier means chemical moiety such that the conjugated amphetamine or any person (other than a medical care worker), business, methylphenidate must undergo a conversion in a patients charitable organization, governmental organization, or other body to become the active amphetamine or methylphenidate entity involved in the transfer of active agent between entities, form. Amphetamine' includes dextro and levo amphetamine for profit or not. Examples of pharmaceutical Suppliers forms and all pharmaceutically acceptable amphetamine include pharmaceutical distributors, pharmacies (online or salts. Conversion typically involves metabolism. “Meth physical), foreign businesses or individuals importing active ylphenidate' also includes all methylphenidate optical iso agent into the United States, the hospitals, HMOs and the mers and all pharmaceutically acceptably methylphenidate Veterans Administration. salts. For example “methylphenidate includes pure dexm 0046 “Pharmaceutically acceptable salts' includes ethylphenidate (C-phenyl-2-piperidineacetatehydrochloride, derivatives of the disclosed compounds, wherein the parent (R,R)-(+)-) and racemic mixtures of d- and 1-methylpheni compound is modified by making non-toxic acid or base date forms. addition salts thereof, and further refers to pharmaceutically 0040 Lisdexamfetamine dimesylate, CAS Reg. No. acceptable solvates, including hydrates, of Such compounds 608137-32-3, (2S)-2,6-diamino-N-(1S)-1-methyl-2-phe and Such salts. Examples of pharmaceutically acceptable nylethylhexanamide dimethanesulfonate, is an amphet salts include, but are not limited to, mineral or organic acid amine prodrug in which L-lysine is covalently bound to d-am addition salts of basic residues such as amines; alkali or phetamine. Lisdexamfetamine dimeSylate is sold under the organic addition salts of acidic residues such as carboxylic trade name VYVANSE (Shire). It has the chemical formula: acids; and the like, and combinations comprising one or more of the foregoing salts. The pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of NH the parent compound formed, for example, from non-toxic H N inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids such as hydro --~~ NH2 chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric O and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts. 0047 Pharmaceutically acceptable organic salts include "Lisdexamfetamine' is typically administered as a dimesy salts prepared from organic acids such as acetic, trifluoroace late salt but includes all pharmaceutically acceptable salts of tic, propionic. Succinic, glycolic, Stearic, lactic, malic, tar lisdexamfetamine free base. The term “lisdexamfetamine' taric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe also encompasses all polymorphs and hydrates of this drug. nylacetic, glutamic, benzoic, salicylic, mesylic, esylic, 0041) “Informing in any of the above embodiments of the besylic, Sulfanilic, 2-acetoxybenzoic, fumaric, toluene invention may occur by reference to, or providing, informa Sulfonic, methanesulfonic, ethane disulfonic, oxalic, tion material. Informing can also occur by presentation at a isethionic, HOOC-(CH), COOH where n is 0-4, and the seminar, conference, or other educational presentation; or by like; organic amine salts such as triethylamine salt, pyridine providing an active agent with informational material to a salt, picoline salt, ethanolamine salt, triethanolamine salt, user, or in a conversation between a pharmaceutical sales dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, representative and a medical care worker or between a medi and the like; and amino acid salts such as arginate, aspargin cal care worker and a patient. ate, glutamate, and the like, and combinations comprising one 0042 “Informational material' means any media provid or more of the foregoing salts. ing information. Media includes printed, audio, visual, or 0048 "Providing includes giving, selling, distributing, electronic media. Examples of information material are flyer, transferring (for profit or not), manufacturing, compounding an advertisement, a package insert for a pharmaceutical prod or dispensing. uct, printed labeling, an internet web site, an internet web 0049. A "product' or “pharmaceutical product' is a dos page, an internet pop-up window, or information recorded on age form of an active agent plus published material and a compact disk, DVD, an audio recording, or any other optionally packing. recording or electronic medium. 0050 “Safety” means the incidence of adverse events 0043. A “medical care worker” means any worker in the associated with administration of an active agent, including health care field who may need information regarding an adverse effects associated with patient-related factors (e.g., US 2013/0045979 A1 Feb. 21, 2013

age, gender, ethnicity, race, target illness, abnormalities of pared via the general methods described in U.S. Pat. No. renal or hepatic function, co-morbid illnesses, genetic char 7,105,486 for the preparation of amphetamine amino acid acteristics such as metabolic status, or environment) and prodrugs. Amino acid methylphenidate prodrugs may com active agent-related factors (e.g., dose, plasma level, duration prise methylphenidate covalently bound to a single amino of exposure, or concomitant medication). acid at the piperidine nitrogen or bound to a di- or tri-peptide 0051. The term “therapeutically effective amount” or at this position. It is also a matter of routine organic synthesis “effective amount’ means an amount effective, when admin to prepare carboxamide and carbamate methylphenidate pro istered to a human or non-human patient, to provide any drugs by reacting methylphenidate with analiphatic aldehyde therapeutic benefit. A therapeutic benefit may be an amelio or aliphatic organic acid. ration of symptoms, e.g., an amount effective to decrease the 0056 Methylphenidate contains a secondary amine group symptoms of binge-eating disorder or a major depressive and amphetamine contains an amino group both of which disorder. In certain circumstances a patient may not present may be reacted to form prodrugs having a chemical moeity symptoms of a condition for which the patient is being covalently attached to the amine or amino group of the parent treated. Thus a therapeutically effective amount of a com drug compound. Prodrugs of amine-containing compounds pound is also an amount Sufficient to provide a significant have been disclosed in U.S. Patent Application No. 2007/ positive effect on any indicia of a disease, disorder or condi 0123468, which is hereby incorporated by reference at para tion e.g. an amount Sufficient to significantly reduce the fre graphs 0078-0137 for its teaching regarding general quency and severity of binge eating behavior or depressive classes of amine prodrugs, at paragraph 0140 for its teach symptoms. A significant effect on an indicia of a disorder or ing regarding amphetamine and methylphenidate prodrugs, condition includes a statistically significant in a standard at paragraphs (0176-0181 for its teachings of methylpheni parametric test of statistical significance such as Students date prodrug structures, and at paragraphs 0184-0189 for T-test, where p-0.05; though the effect need not be significant its teaching regarding prodrugs synthesis. in Some embodiments. 0052 A “user' is a patient, a medical care worker, or a Methylphenidate Analogs pharmaceutical Supplier. 0057 Methylphenidate analogs are compounds have a Amphetamine and Methylphenidate Prodrugs structure highly similar to methylphenidate, and like meth ylphenidate bind to the brain dopamine transporter and affect 0053 Amphetamine has the chemical formula the reuptake of dopamine in the brain, but which have an extended duration of action relative to methylphenidate. Methylphenidate analogs include compounds having the gen eral formula

0054 Amphetamine prodrugs, and methods of preparing amphetamine prodrugs have been described previously. U.S. Pat. No. 7,105,486, which describes the preparation of lis dexamfetamine, is hereby incorporated by reference at cols. 20 to 22 for its teachings regarding the synthesis of amino acid amphetamine prodrugs. In addition to amino acid pro where at least one of R and R is a non-hydrogen Substituent drugs it is possible to prepare a number of other amphetamine differing from the group that occurs at the corresponding prodrugs by reacting the amphetamine amino group with a position in methylphenidate and R and Rs are independently chemically labile moiety. It is within the ability of those of chosen from hydrogen, halogen, hydroxyl, C-C alkyl, and ordinary skill in the art of chemical synthesis to prepare C-Calkoxy, and the like. Methylphenidate analogs have carboxamide amphetamine prodrugs by reacting amphet been disclosed in U.S. Non-provisional Patent Application amine with an aliphatic aldehyde and to prepare carbamate No. 2006/0100243, which is hereby incorporated by refer amphetamine prodrugs by reacting amphetamine with an ali ence at paragraphs 0007-0021 for its teachings regarding phatic organic acid. the methylphenidate analog structures, at paragraphs 0055 0055 Methylphenidate has the chemical formula 0063 for its teachings regarding the methylphenidate analog structure and synthesis, and at paragraphs 0083-0085 for

its exemplary synthesis of methylphenidate analogs.

Methods of Treatment 0058. The invention provides methods of treating binge eating disorders, obesity resulting from binge eating behav ior, and depression. The invention includes methods of treat ing certain co-morbidities in ADHD and ADD patients; the invention includes methods of treating generalized anxiety disorder, obsessional and ruminative thought disorders, and The arrow indicates a chemically accessible site at which obsessive/compulsive behavior in patients, particularly in labile groups may be added to create methylphenidate pro ADHD and ADD patients. The amphetamine prodrug, meth drugs. Amino acid methylphenidate prodrugs may be pre ylphenidate prodrug, or methylphenidate analog may be the US 2013/0045979 A1 Feb. 21, 2013

only active agent administered (monotherapy) or may be often worse later in the day. Problems with concentration or combined with one or more other active agents (combination, fatigue, associated with depression or which may be associ adjunct, or augmentation therapy). ated with other conditions, may receive notably significant 0059. The invention also provides methods of treating benefit as well. Additionally, treatment of binge eating behav depression, weight gain and/or obesity associated with ior with lisdexamfetamine dimeSylate, where symptoms may depression, and weight gain and/or obesity due to taking intensify toward the end of the day or in the evening or may antidepressant medications. have some relation to feelings of dysphoria as other stimulant 0060. The invention provides a method of treating chronic medications wear off, would achieve Surprisingly positive fatigue syndrome, fatigue, amotivation, or cognitive deficits benefit. Lisdexamfetamine dimesylate is thought to confer associated with fatigue comprising diagnosing a patient as less euphorgenic properties, which may also mitigate feel having chronic fatigue syndrome, fatigue, amotivation or ing down as the medication “wears off.” cognitive deficits associated with fatigue and providing an 0.066 Lisdexamfetamine dimesylate, sold under the trade effective amount of amphetamine prodrug, methylphenidate name VYVANSE (Shire), is FDA approved for the treatment prodrug, or methylphenidate analog to the patient. of Attention-Deficit Hyperactivity Disorder. Other psycho 0061. In a first embodiment the invention includes a stimulant treatments for Attention-Deficit Hyperactivity Dis method of treating binge eating disorder or obesity resulting order include both amphetamine (e.g. ADDERALL and from binge eating behavior, comprising diagnosing a patient ADDERALL XR) and methylphenidate (e.g. RITALIN and as having a binge eating disorder or obesity resulting from CONCERTA) preparations. Stimulant drugs, including lis binge eating behavior and providing an effective amount of dexamfetamine dimeSylate, are believed to act via potentia amphetamine prodrug, methylphenidate prodrug, or meth tion of dopamine and norepinephrine neurotransmission in ylphenidate analog to the patient, wherein the amphetamine the central nervous system. prodrug, methylphenidate prodrug, or methylphenidate ana 0067 Amphetamine prodrugs, including lisdexamfe log is provided as the only active agent or is provided together tamine, methylphenidate prodrugs, and certain methylpheni with one or more additional active agents. date analogs are unexpectedly effective for treating a number 0062. In another embodiment the invention provides a of disorders exacerbated by non-chemically modified imme method of treating depression comprising (i) diagnosing a diate release and extended release amphetamine and meth patient as having depression and (ii) providing an effective ylphenidate including binge eating disorder and depression. amount of amphetamine prodrug, methylphenidate prodrug, In certain embodiments a patient is diagnosed as having a or methylphenidate analog to the patient, wherein the binge eating disorder or obesity related to binge eating behav amphetamine prodrug, methylphenidate prodrug, or meth ior and an amount of amphetamine prodrug, methylphenidate ylphenidate analog is provided as the only active agent or is prodrug, or methylphenidate analog is provided to the patient; provided together with one or more additional active agents. wherein the amount is effective to reduce the number of binge 0063) Psychosocial intervention may play an important eating episodes in a one month time period, to produce a role intreatment of both depression and binge eating disorder. weight loss of 5% or greater of the patient’s body mass within Psychosocial intervention includes cognitive-behavior a six month treatment period, or significantly reduce the therapy, dialectical-behavior therapy, interpersonal therapy, patient’s triglyceride levels by 20% or more over a six month psychodynamic therapy and group therapy. treatment period. 0064. While amphetamine and methylphenidate based 0068 Methods of treatment include administering an stimulant medications have been associated with the side effective amount of an amphetamine prodrug, methylpheni effect of appetite Suppression and enhanced mood, their date prodrug, or methylphenidate analog wherein the effec release mechanisms are of short or intermediate duration. As tive amount is an amount effective to decrease the number of plasma levels of these drugs drop, patients typically experi binge eating episodes per month or decrease the number of ence symptoms associated with low drug levels. Even days in a month in which the patient experiences a binge extended release amphetamine or methylphenidate formula eating episode. tions leave individuals with a wear off effect for a sufficient 0069. In other embodiments the effective amount of part of the day, in which the medication loses its effects amphetamine prodrug, methylphenidate prodrug, or meth including appetite suppressant properties. Wear off effects ylphenidate analog is an amount effective to decrease depres lead to problematic symptoms or side effects, sometimes of a sive symptoms. Preferably the decrease in depressive symp rebound nature, including the urge to have more medication, toms is a 50% or greater reduction of symptoms identified on feeling dysphoric or low, feeling hungry or eating more, binge depression symptom rating scale or is constituted by a depres eating, fatigue, amotivation, and poor concentration. sion symptom rate scale score below a particular value that 0065 Lisdexamfetamine dimesylate, given its slower and may signify remission of a depressive episode (for instance, gradual release, confers certain significant advantages not less than or equal to 7 on the HRSD7). seen previously with other amphetamine or methylphenidate 0070 The invention provides methods of treating weight stimulants. There is minimal wear-off effect, a smoother gain associated with depression or caused by treatment with distribution of drug over time, and no apparent need for antidepressant medications. dosing beyond once per day as significant effects have been 0071 Treatment approaches for major depressive disorder demonstrated for up to 12 hours after administration. The or other disorders in which depressive symptoms are present unique clinical profile of lisdexamfetamine dimesylate offers typically do not include the management of obesity. Simi all the benefits of a stimulant treatment for a full day, a larly, treatment approaches for obesity typically do not much-needed advance required for Sustained clinical benefit address depressive symptoms. Pharmacologic treatments for in depressive and binge eating disorders. Such a profile is mood disorders may actually contribute to weight gain, obe particularly significant for depressive disorders, where a low sity, or increased abdominal girth, with potentially untoward mood is characteristically present through the entire day and psychological effects or medical sequelae Such as hypertrig US 2013/0045979 A1 Feb. 21, 2013 lyceridemia, metabolic syndrome, or type II diabetes. While once per day is preferred. Dosage regimens in which the the mood disorder or depressive symptoms may be effectively amphetamine prodrug or methylphenidate prodrug is admin treated with Such pharmacologic agents, associated weight istered 2 times daily may occasionally be more helpful. In gain can carry a number of serious risks. Treatments that certain embodiments, 2.5 mg to 250 mg lisdexamfetamine address both depression and obesity, as either monotherapy or dimesylate is administered per day or 15 to 100 mg lisdex as adjunct treatment, are much needed clinically and would amfetamine dimesylate per day, or about 50 mg per day serve a population with unmet clinical needs. Further, as lisdexamfetamine dimesylate is administered. Lisdexamfe demonstrated by the putative link of binge eating to Such tamine dimesylate is typically administered once daily in the conditions as depression and obesity, pharmacologic inter morning, with preferred dosing in the range of 15-70 mg per ventions that ameliorate binge eating may have particular day, though in Some embodiments daily doses of less than 15 added value. mg, for example from about 2.5 mg to about 15 mg, or from 0072 The relationship between mood disorders and obe about 2.5 to about 12.5 mg are useful for treating binge eating sity has been examined in a number of clinical and demo behaviors or depression. graphic studies, though the relationship is complicated and 0075. It will be understood, however, that the specific dose poorly understood. Current paradigms that link the two con level for any particular patient will depend upon a variety of ditions Suggest the possibility that shared genetic Vulnerabili factors including the activity of the specific compound ties, neurobiology (in particular the hypothalamic-pituitary employed, the age, body weight, general health, sex, diet, adrenocortical HPAC axis), or social factors may play time of administration, route of administration, rate of excre important roles. Demographic studies suggest obesity, tion, drug combination and the severity of the particular dis including associated conditions of overweight and abdomi ease in the patient undergoing therapy. Patients may generally nal obesity, are common to patients treated for mood disor be monitored for therapeutic effectiveness using assays Suit ders and represent a risk factor for depression, in particular able for the condition being treated or prevented, which will for females, children, and individuals with child-onset major be familiar to those of ordinary skill in the art. depression. It is well established that major depressive disor der commonly will present with atypical features, as recog Combination Methods nized in the DSM-IV-TR, with symptoms of weight gain, low 0076. The invention provides a method of treating of cen energy, and inactivity. Binge eating symptoms may also tral nervous system disorders in which an amphetamine pro accompany such forms of depression. Interestingly, obese drug, methylphenidate prodrug, or methylphenidate analog is individuals with binge eating disorder or behavior have been provided to a patient together with one or more additional shown to have higher rates of mood disorders. There is active agents. Such methods are referred to as “combination research to suggest that women having major depressive dis methods” of treatment. Combination methods of treating order may be particularly disposed to weight gain and obesity binge eating disorders, obesity resulting from binge eating and, as such, may represent either a distinct Subset of depres behavior, and depression are included herein. The invention sion or of obesity, which may even be linked to polycystic includes combination methods of treating certain co-morbidi ovarian syndrome. More recent data Suggests an even more ties in ADHD and ADD patients; for example the invention conclusive link between obesity and atypical features of includes combination methods of treating generalized anxi depression in women with bipolar disorder. In fact, the DSM ety disorder, obsessional and ruminative thought disorders, IV-TR recognizes that atypical features of depression are and obsessive/compulsive behavior in ADHD and ADD 2-3 times more common in women than in men. patients. 0073. The invention further includes methods of using 0077. The additional active agent may be administered lisdexamfetamine dimeSylate, comprising informing a user separately from the amphetamine prodrug, methylphenidate that the lisdexamfetamine dimesylate may be used to treat prodrug, or methylphenidate analog or may be combined with binge eating disorders, obesity resulting from binge eating the additional active agent. behavior, or depression. The invention includes methods of 0078. The invention also includes combination methods using lisdexamfetamine dimesylate comprising informing a of treatment in which an amphetamine prodrug, methylpheni user that the lisdeXamfetamine dimeSylate may be used to date prodrug, or methylphenidate analog is administered treat certain co-morbidities in ADHD and ADD patients, together with one or more forms of therapy, psychosocial including methods of treating generalized anxiety disorder, Support, or medical management. Such forms of psychosocial obsessional and ruminative thought disorders, and obsessive/ intervention include cognitive-behavior therapy, dialectical compulsive behavior in ADHD and ADD patients. The user behavior therapy, interpersonal therapy, psychodynamic may be informed of the usefulness of lisdexamfetamine therapy and group therapy. dimesylate, or other amphetamine prodrug, a methylpheni 0079. The invention also includes combination methods date prodrug, or a methylphenidate analog for the treatment of treatment in which the one or more other active agent(s) is of the above-mentioned disorders and conditions by refer an appetite Suppressant, a weight loss drug, an anti-obesity ence to a package insert associated with the container. The agent, an anti-diabetes agent, an antidepressant, an anxi informing may also be by reference to information material; olytic, a selective serotonin reuptake inhibitor, a serotonin by reference to a package active agent insert, a flyer or an 5HT receptor partial agonist or antagonist, a norepinephrine advertisement; by presentation of information at a seminar, dopamine reuptake inhibitor, a serotonin norepinephrine conference, or other educational presentation; or by a conver dopamine reuptake inhibitor, a serotonin 5-HT1a partial ago sation between a pharmaceutical sales representative and a nist, a serotonin 5-HT1b agonist, a serotonin 5-HT2 antago medical care worker. nist, a serotonin 5-HT6 antagonist, a serotonin-2 antagonist 0074 Frequency of dosage may vary depending on the reuptake inhibitor, a serotonin-1 agonist reuptake inhibitor, a compound used and the particular condition or disorder to be mixed serotoninantagonist reuptake inhibitor/partial agonist/ treated or prevented. For most disorders a dosage regimen of dopamine agonist, an alpha-2 antagonist/serotonin 5HT2-3 US 2013/0045979 A1 Feb. 21, 2013 receptor antagonist, a serotonin modulator or stimulator, a 0090 Norepinephrine dopamine reuptake inhibitors mixed serotonin antagonist/melatonin agonist, a mixed sero include, but are not limited to bupropion. tonin dopamine antagonist, a tricyclic antidepressant, a tetra 0091 Tricyclic antidepressants include, but are not lim cyclic antidepressant, a bis-aryl-Sulphanyl modulator, a ited to, doxepin, amitriptyline, amoxapine, clomipramine, beta-3 adrenoreceptor stimulator or agonist, a beta-3 adreno desipramine, doxepin, imipramine, maprotiline, nortrip receptorantagonist, a nicotinic acetylcholine receptoragonist tyline, protriptyline, and trimipramine. or antagonist, an enkephalinergic modulator, an aprepitant, a 0092 Benzodiazepines include but are not limited to, neurokinin (NK) antagonist, a NK1, 2, or 3 antagonist, a alprazolam, clonazepam, diazepam, lorazepam, flurazepam, neuropeptide (NP)Yantagonist, a NPY1, 2, or 3, or 5 antago and bentazepam. nist, a Substance Pantagonist, a corticotrophin-releasing hor 0093 Anti-manics include, but are not limited to, carbam mone (CRH or CRF) antagonist, a CRH (or CRF)-1 antago azepine, Valproic acid and lithium. nist, a glucocorticoid receptor agonist or partial agonist, a glucocorticoid receptor antagonist, a glucocorticoid receptor 0094 Alpha-2 receptor agonists include but are not lim type II antagonist, an anti-convulsant, a GABA modulator, a ited to guanfacine and clonidine. GABA inverse agonist or partial agonist, a GABA receptor 0.095 Wakefulness promoting agents include but are not antagonist, a GABA channel antagonist, a GABA reuptake limited to modafinil and arrinodafinil. inhibitor, a glutamate modulator, an mGluR receptor modu 0096 Neurokinin-1 antagonists includebut are not limited lator, agonist or antagonist, an mGluR2/3 agonist, an to casopitant. mGluR5 antagonist, an estrogen receptor agonist or antago 0097 Neurokinin-2 antagonists includebut are not limited nist, a melatonin receptor agonist or antagonist, a glycine to saredutant. transporter inhibitor, an alpha-1 receptor agonist, an alpha-1 0098. Beta-3 adrenoreceptor agonists include but are not receptor antagonist, an alpha-2 receptor agonist, an alpha-2 limited to amibegron. receptor antagonist, a vasopressin-1B (V1B) agonist or 0099 CRF1 antagonists include but are not limited to antagonist, an NMDA receptor modulator (i.e., a partial ago pexacerfont. nist, agonist, or antagonist), an ampakine modulating agent, 0100. An anti-obesity agent may include a cannaboid an opioid antagonist, an opioid partial agonist, a benzodiaz receptor ligand, antagonist, or inverse agonist; a fatty acid epine, an anti-psychotic, a dopamine receptor agonist orana amide hydrolase inhibitor; a peptide YY: a serotonin 5-HT2c log, a Wakefulness promoting agent, an anti-manic agent, a antagonist; an adipocyte 11B-hydroxysteroid dehydrogenase mood modulating (i.e., stabilizing) agent, a cholinesterase type 1 antagonist; an amylase inhibitor, an anti-angiogenesis inhibitor, an anti-amyloid agent, an anti-aggregant, a beta inhibitor; an agouti-related peptide analog, agonist, or secretase inhibitor, a beta-amyloid antagonist, a monoamine antagonist; a carboxypeptidase inhibitor, a ciliary neu oxidase inhibitor, an anti-migraine agent, a melanocyte inhib rotrophic factor; a cholecystokinin (CCK) analog, agonist or iting factor, or a combination of the foregoing. inhibitor; a corticotrophin relating hormone modulator, ago 0080 Weight-loss drugs include, but are not limited to, nist, or antagonist; a CKGGRAKDC peptide; a dehydroepi lipase inhibitors. Non-limiting examples of weight loss drugs androsterone analog; a fatty acid synthesis inhibitor; a fat include orlistat. targeted peptide; a G-protein coupled receptor (GCPR) 0081 Anti-diabetes drugs include, but are not limited to, modulator; a gastrointestinallipase inhibitor, aghrelin modu hypoglycemic agents. Non-limiting examples include acar lator, agonist orantagonist; a human growth hormone (HGH) bose, chlorpromide, exenatide, gliclazide, glimepiride, glip analog or fragment; a growth harmone secrectogue receptor izide, glyburide, insulin, metformin, miglitol, nateglinide, (GHS-R) modulator, agonist orantagonist; a lipase inhibitor; pioglitaZone, pramlintide, repaglinide, rosiglitaZone, and a leptin analog, transport and/or receptor promoter, a melano tolaZamide. cortin (MC) receptor agonist or antagonist; an M4 receptor 0082 Anti-psychotics include atypical anti-psychotics. agonist or antagonist; a melanin concentrating hormone Non-limiting examples of anti-psychotics include clozapine, (MCHR) agonist orantagonist; a melanocyte stimulatinghor olanzapine, risperidone, aripiprazole, quetiapine, paliperi mone analog; a neuropeptideY modulator, agonist orantago done, Ziprasidone, and amisulpride. nist; a thyroid hormone; 0.083 Anti-convulsants include, but are not limited to, a thyroid receptor agonist; an orexin modulator, agonist or anti-epileptics and anti-seizure medications. Non-limiting antagonist; a peptide YY or related analog or stimulator, a examples of anti-convulsants include topiramate, lamot phytostanol analog; a pro-opiomelanocortin (POMC) Stimu rigine, pregabalin, tiagabine, and Zonisamide. lator, a Somatostatin agonist; or a TNF-alpha antagonist. 0084. Selective serotonin reuptake inhibitors include, but 0101. An anti-diabetes agent may include a glucose-low are not limited to, citalopram, escitalopram, femoxetine, flu ering (i.e., hypoglycemic) agent; an alpha-glucosidase inhibi oxetine, fluvoxamine, paroxetine, Sertraline, and Zimeldine. tor; an amylin analog; a biguanide; an incretin mimetic or 0085 Serotonin partial agonists include, but are not lim analog; a glucagon-like peptide-1 (GLP-1) agonist or analog: ited to, pindolol, gepirone, and flesinoxan. a dipeptidyl peptidase (DPP) inhibitor; a DPP-IV inhibitor; a I0086) Selective serotonin norepinephrine reuptake inhibi glucose-dependent insulinotropic peptide (GIP) agonist or tors include, but are not limited to, dulloxetine, Venlafaxine, analog; a gastric inhibitory peptide analog; a form of insulin desvenlafaxine, milnacipran, and clovoxamine. (ie, injectable or inhaled); a fructose 1.6 biphosphatase (FB 0087 Norepephrine reuptake inhibitors include, but are Pase) inhibitor; a meglitinide; a peroxysome proliferators not limited to, atomoxetine and reboxetine. activated receptor (PPAR) modulator, agonist orantagonist; a 0088 Serotonin-2 antagonist reuptake inhibitors include, PPAR-gamma agonist orantagonist; a protein-tyrosine phos but are not limited to, trazodone. phatase (PTP) 1B modulator, agonist orantagonist; a sodium 0089 Alpha-2 antagonist/serotonin 5HT2-3 receptor dependent glucose transporter (SGLT) inhibitor; a sulfony antagonists include, but are not limited to, mirtazapine. lurea; or a thiazolidinedione (ie, a 'glitaZone'). US 2013/0045979 A1 Feb. 21, 2013

0102 The invention includes combination methods of comprising an amphetamine prodrug, methylphenidate pro treatment in which an amphetamine prodrug, Such as lisdex drug, or methylphenidate analog in a container and printed amfetamine dimesylate, a methylphenidate prodrug, or a labeling stating that the amphetamine prodrug, methylpheni methylphenidate analog is provided together with a Norepi date prodrug, or methylphenidate analog is useful for treating nephrine/Dopamine Reuptake Inhibitor, a Serotonin a binge eating disorder or associated symptoms, obesity Reuptake Inhibitor, a Selective Serotonin Norepinephrine resulting from binge eating behavior, or depression. Reuptake Inhibitor, a Norepinephrine Reuptake Inhibitor, or 0107. When an article of manufacture of this invention an Anticonvulsant. For example the invention includes com comprises lisdexamfetamine dimesylate, the labeling may bination methods in which the amphetamine prodrug (e.g. advise administering 2.5 mg to 250 mg, 2.5 mg to 12.5 mg. lisdexamfetamine dimeSylate) or methylphenidate prodrug is 2.5 to 15 mg, 10 to 100 mg per day, 20 to 70 mg per day, or provided in combination with one or more of bupropion HCl, about 50 mg per daylisdexamfetamine dimesylate. The label Venlafaxine, paroxetine, mirtazapine, dulloxetine, citalopram, ing may advise that lisdexamfetamine dimesylate is to be escitalopram, fluoxetine, Sertraline, atomoxetine, topiramate, administered once daily, but there may be clinical value in Zonisamide, lamotrigine, gabapentin, tiagabine, or pregaba Some patients for up to two times per day. lin. 0103) When treating binge eating the following active Pharmaceutical Preparations agents are particularly useful in combination with a meth 0108. An amphetamine prodrug, methylphenidate pro ylphenidate prodrug or amphetamine prodrug: orlistat, drug, or methylphenidate analog alone or in combination with bupropion, memantine, naltrexone, acamprosate, topiramate, one or more other active agent(s) can be administered as the Zonisamide, sibutramine. Sibutramine may not be suitable for neat chemical, but is preferably administered as a pharma all patients because of its tendency to elevate pulse and blood ceutical composition or formulation. Accordingly, the inven pressure. Zonisamide is effective for treatment of binge eat tion provides pharmaceutical formulations comprising an ing but is not always well tolerated. amphetamine prodrug, methylphenidate prodrug, or meth 0104. When treating depression the following active ylphenidate analog alone or in combination with one or more agents are particularly useful in combination with a meth other active agents together with one or more pharmaceuti ylphenidate prodrug or amphetamine prodrug: excitalopram, cally acceptable carriers. Pharmaceutical formulations com Sertraline, fluoxetine, citalopram, bupropion, Venlafaxine, prising lisdexamfetamine dimesylate have been previously and duloxetine. described in U.S. Pat. No. 7,105,486, which is hereby incor porated by reference at cols. 13 to 17 for its teachings regard Articles of Manufacture ing amphetamine prodrug formulations including lisdexam 0105. The invention includes articles of manufacture, fetamine dimesylate formulations. which comprise an amphetamine prodrug, methylphenidate 0109 An amphetamine prodrug, methylphenidate pro prodrug, or methylphenidate analog in a container and label drug, or methylphenidate analog alone or in combination with ing stating that the amphetamine prodrug, methylphenidate one or more other active agent(s) may be administered orally, prodrug, or methylphenidate analog is effective for treating topically, parenterally, by inhalation or spray, Sublingually, certain central nervous system disorders; including treating transdermally, via buccal administration, or by other means, binge eating disorders, obesity resulting from binge eating in dosage unit formulations containing conventional non behavior, and depression. The labeling may also state that the toxic pharmaceutically acceptable carriers, excipients, adju amphetamine prodrug, methylphenidate prodrug, or meth vants, and vehicles. Oral dosages forms such as tablets, tro ylphenidate analog is effective for treating certain co-mor ches, lozenges, aqueous or oily Suspensions, dispersible bidities in ADHD and ADD patients; for example the inven powders or granules, emulsions, hard or soft capsules, or tion includes methods of treating generalized anxiety syrups or elixirs are preferred. Oral administration is pre disorder, obsessional and ruminative thought disorders, and ferred for lisdexamfetamine dimesylate administration. In obsessive/compulsive behavior in ADHD and ADD patients. Some embodiments solid oral dosage forms are preferred. The amphetamine prodrug, methylphenidate prodrug, or Tablets, capsules, and inhalable (e.g. intranasal) preparations methylphenidate analog present in this article of manufacture are preferred. Compositions intended for oral use may be may be lisdexamfetamine dimeSylate or some other amphet prepared according to any method known to the art for the amine prodrug, methylphenidate prodrug, or methylpheni manufacture of pharmaceutical compositions and Such com date analog. The article of manufacture may comprise the positions may contain one or more agents, such as Sweetening amphetamine prodrug, methylphenidate prodrug, or meth agents, flavoring agents, coloring agents and preserving ylphenidate analog as the only active agent or may include agents, in order to provide pharmaceutically elegant and pal one or more additional active agents. Additional active agents atable preparations. may be combined in a single dosage form with the amphet 0110 Oral formulations contain between 0.1 and 99%, at amine prodrug, methylphenidate prodrug, or methylpheni least about 5% (weight%), 25% to about 50% or from 5% to date analog or may be packaged as separate dosage forms. 75% of an amphetamine prodrug, methylphenidate prodrug, The article of manufacture may comprise packaging material or methylphenidate analog alone or in combination with one and a dosage form of an amphetamine prodrug, methylpheni or more other active agent(s) and usually at least about 5% date prodrug, or methylphenidate analog contained within the (weight%) of a compound of the present invention. packaging material, wherein the packaging material com 0111. In addition to the amphetamine prodrug, meth prises a label approved by a regulatory agency for the product. ylphenidate prodrug, or methylphenidate analog alone or in In certain embodiments the labeling is labeling approved by combination with one or more other active agent(s), the com the United States FDA. positions of the invention may contain a pharmaceutically 010.6 An example of an article of manufacture provided acceptable carrier, one or more compatible solid or liquid by the invention is a packaged pharmaceutical compositions filler diluents or encapsulating Substances, which are Suitable US 2013/0045979 A1 Feb. 21, 2013

for administration to an animal. Carriers must be of suffi 2.5 to 200 mg methylphenidate prodrug together with lactose, ciently high purity and sufficiently low toxicity to render magnesium Stearate, polyethylene glycol, starch, Sucrose, them suitable for administration to the animal being treated. talc, and gum tragacanth. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in con EXAMPLES junction with the compound is Sufficient to provide a practical quantity of material for administration per unit dose of the 0116. The following examples describe patients with compound. binge eating disorder or associated symptoms, a history of major depressive episodes, obsessive compulsive behavior, 0112 The pharmaceutical dosage forms may contain an generalized anxiety disorder, or attention deficit hyperactiv amphetamine prodrug, methylphenidate prodrug, or meth ity disorder whose symptoms were poorly managed with ylphenidate analog as the only active agent or may be com psychopharmacologic interventions. In the cases wherebinge bined with one or more additional active agents in the same eating and depression were present, binge eating behavior dosage form. Active agents Suitable for combination with an significantly lessened following treatment with the amphet amphetamine prodrug, methylphenidate prodrug or meth amine prodrug, lisdeXamfetamine dimesylate; in one of these ylphenidate analog in a single dosage form have been listed cases, it was thought that binge eating symptoms were due to above in the section titled “Combination Methods.” Particu antidepressant medication and the addition of amphetamine larly useful combination dosage forms include lisdexamfe prodrug lisdexamfetamine dimeSylate decreased binging tamine in combination with at least one of the following in a behavior. Additionally, patients treated with lisdexamfe single dosage form: orlistat, memantine, naltrexone, acamp tamine dimeSylate, either as a monotherapy or as an adjunct to rosate, topiramate, Zonisamide, Sibutramine, escitalopram, existing therapies, experienced remission of their depressive Sertraline, fluoxetine, citalopram, bupropion, Venlafaxine, symptoms. The examples demonstrate the effectiveness of an and duloxetine. amphetamine prodrug as a monotherapy or in combination with one or more other therapeutic agents for treating a range Tablets and Capsules of psychological symptoms, including binge eating and depression. 0113 Tablets typically comprise conventional pharma 0117 These case reports suggest the clinical efficacy of an ceutically compatible adjuvants as inert diluents, such as amphetamine prodrug, methylphenidate prodrug, or meth calcium carbonate, sodium carbonate, mannitol, lactose and ylphenidate analog in the treatment of binge eating disorder cellulose; binders such as starch, gelatin and sucrose; disin or associated symptoms (in two cases thought to worsen from tegrants such as starch, alginic acid and croScarmelose; lubri antidepressant agents), obesity resulting from binge eating cants such as magnesium Stearate, Stearic acid and talc. behavior, and depressive disorders, as either a monotherapy Glidants such as silicon dioxide can be used to improve flow or as an adjunct to existing antidepressant pharmacotherapy. characteristics of the powder mixture. Coloring agents, such In addition these cases also demonstrate that an amphetamine as the FD&C dyes, can be added for appearance. Sweeteners prodrug, a methylphenidate prodrug, or methylphenidate and flavoring agents, such as aspartame, Saccharin, menthol, analog may offer significant clinical value in treatment of peppermint, and fruit flavors, are useful adjuvants for chew anxiety spectrum symptoms, include generalized anxiety dis able tablets. Capsules (including time release and Sustained order and obsessive compulsive behavior. release formulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components Example 1 often depends on secondary considerations like taste, cost, and shelf stability. Such compositions may also be coated by Treatment of a Patient with Major Depressive conventional methods, typically with pH or time-dependent Disorders and Binge Eating Disorder Using the coatings, such that the Subject compound is released in the Amphetamine Prodrug Lisdexamfetamine gastrointestinal tract in the vicinity of the desired topical Dimesylate application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, 0118 Patient 1 is an adult, non-geriatric patient with a one or more of cellulose acetate phthalate, polyvinylacetate history of a major depressive disorder, attention deficit hyper phthalate, hydroxypropyl methylcellulose phthalate, ethyl activity disorder, and binge eating disorder. Throughout cellulose, Eudragit coatings, waxes and shellac. Patient 1s entire adult life, there were reportedly periodic depressive episodes and symptoms. Patient 1 also indicated a 0114 Formulations for oral use may also be presented as history of binge eating disorder for approximately one year, hard gelatin capsules wherein the active ingredient is mixed characterized by eating unusually large amounts of junk food, with an inert Solid diluent, for example, calcium carbonate, often until feeling nauseated, and then feeling very guilty calcium phosphate or kaolin, or as Soft gelatin capsules about the binging behavior. Such symptoms, though intermit wherein the active ingredient is mixed with water or an oil tently present for the past two decades, had escalated to an medium, for example peanut oil, liquid paraffin or olive oil. average of nearly every other day for about 12 months. During 0115 The invention includes amphetamine prodrug cap this time Patient 1 was being treated with PAXIL (paroxetine) Sule formulations, particularly lisdexamfetamine dimesylate and then ZOLOFT (sertraline) daily. Patient 1 participated in capsule formulations, 2.5 mg to 250 mg, 2.5 mg to 12.5 mg. group therapy to address mood and eating symptoms. How 2.5 to 15 mg, 10 to 100 mg per day, 20 to 70 mg per day, or ever, group therapy did not prove helpful for managing the about 50 mg per day lisdexamfetamine dimeSylate together binging behavior, the number of episodes as well as the with one or more of microcrystalline cellulose, croScarmel number of days binging continued on average every other lose sodium, and magnesium Stearate in a gelatin capsule. The day. Following group therapy, Patient 1 began to experience a invention also includes methylphenidate tablets comprising worsening depressed mood, poor concentration, and exces US 2013/0045979 A1 Feb. 21, 2013 sive feelings of guilt, fatigue, and feelings of hopelessness. binge eating symptoms intensified in the 6 months prior to Prior treatments for this patient’s major depressive disorder starting lisdexamfetamine dimeSylate treatment, occurring at included PROZAC (fluoxetine), LEXAPRO (escitalopram), least two days per week, and causing an approximately 30 EFFEXOR (venlafaxine HCl), and WELLBUTRIN (bupro pound weight gain. Lisdexamfetamine dimesylate treatment pion Hall). Lisdexamfetamine dimesylate was added to was initiated, primarily for treatment of Patient 2s attention Patient 1's 100 mg ZOLOFT (sertraline) therapy as this deficit hyperactivity disorder to provide greater coverage into patient met criteria of attention deficit hyperactivity disorder, the evening, with a dosing schedule of 30 mg on day 1, 50 mg with both inattention and hyperactivity symptoms present on day 2, and 70 mg on day 3, the patient had been taking since childhood, though this diagnosis was not previously Adderall XR30 mg per day, which was discontinued on day made for Patient 1. The dose of lisdexamfetamine dimesylate 1 of starting lisdexamfetamine dimeSylate. The patient was was titrated from 30 mg. to 50 mg. to 70 mg, in three succes maintained on lisdexamfetamine dimesylate for about 10 sive weeks, respectively. Patient 1 reported significant weeks. improvement in the prior symptoms of inattention, forgetful I0121 Patient 2 noted an overall improvement in depres ness, procrastination and physical restlessness, among others, sive symptoms, including depressed mood, general interest by the time Patient 1 was taking 70 mg of lisdexamfetamine level in activities especially in the evenings, sleep quality, and dimesylate daily. Patient 1 was maintained on that dose for an physical fatigue. Patient 2 also noted a marked reduction in ensuing 8 weeks, along with 100 mg ZOLOFT (sertraline), binging episodes, both in terms of the total number and total and reported having no more than 3 or 4 binging episodes in days of binges; Such binging episodes occurred only once in total and no more than 3 hinging days for the 8 weeks that the first 2 weeks of treatment and stopped entirely in the Patient 1 was maintained at 70 mg lisdexamfetamine dime subsequent 8 weeks of treatment with lisdexamfetamine Sylate daily. dimesylate. The patient, considered obese prior to starting 0119 Patient 1 experienced a reduction from approxi lisdexamfetamine dimesylate, lost approximately 7% of total mately 12 or more binge eating days per month, present for body weight while taking the amphetamine prodrug. Interest approximately one year, to no more than 3 per month while ingly, triglyceride levels present prior to taking lisdexamfe taking the amphetamine prodrug lisdeXamfetamine dimesy tamine dimesylate were 271 mg/dL and reduced to 160 late, an approximately 75% reduction of binging eating days mg/dL by the end of 5 weeks of treatment with lisdexamfe per month. Patient 1 also noted full remission of depressive tamine dimesylate. symptoms for the 8 weeks of maintenance on 70 mg lisdex 0.122 This case report exemplifies the utility of an amphet amfetamine dimesylate in addition to 100 mg ZOLOFT (ser amine prodrug as a monotherapy for depression treatment, as traline) noting significant improvement in depressed mood, demonstrated in this patient with an underlying depressive concentration, feelings of guilt, fatigue and no longer expe disorder, untreated with antidepressant medication at the time rienced any sense of hopelessness. of initiating lisdexamfetamine dimesylate, who showed sig nificant improvement across all the patient’s depressive Example 2 symptoms. The effectiveness of lisdexamfetamine dimesy late monotherapy in treating the patient’s treatment resistant Treatment of a Patient with Binge Eating Disorder depression is particularly remarkable in view of Patient 2s and Major Depressive Disorders Using number of failed treatments of recurrent major depressive Lisdexamfetamine Dimesylate disorder. Prior treatments failed due to poor treatment 0120 Patient 2 is a non-geriatric adult with a history of response and medication side effect intolerability. It should attention-deficit hyperactivity disorder, poly Substance be noted that Patient 2s ADHD symptoms were not at issue dependence, major depressive disorder, generalized anxiety at the time lisdexamfetamine dimeSylate monotherapy was disorder, and binge eating disorder. The patient has been begun. The patient’s ADHD symptoms were adequately treated in the past with multiple medication trials, either alone addressed with ADDERALL XR treatment. Lisdexamfe or in combination, including: WELLBUTRIN (bupropion tamine dimesylate monotherapy was started to address the HCl), EFFEXOR (venlafaxine HCl), CELEXA (citalopram), adverse effects Patient 2 had experienced from ADDERALL LAMICTAL (lamotrigine), RISPERDAL (risperidone), XR treatment. Lisdexamfetamine dimesylate proved as effec NEURONTIN (gabapentin), KLONOPIN (clonazepam), tive as ADDERALL XR in addressing the patient’s ADHD STRATTERA (atomoxetine) CONCERTA (methylpheni symptoms, demonstrated Sustained and full day antidepres date), RITALIN SR (methylphenidate), ADDERAL XR sant efficacy, and functioned as an antidepressant in addition (dextroamphetamine--amphetamine), and PROVIGIL to alleviating ADHD symptoms. (modafinil). The patient also was previously treated with Example 3 intensive psychotherapy and received various forms of Sub stance abuse counseling in the past. Lisdexamfetamine dime Treatment of a Patient with ADHD, Generalized sylate was initiated for treatment of the patient’s ADHD to Anxiety Disorder, and Obsessive-Compulsive address wear off effects from ADDERALL XR in the later afternoons and early evenings. While the patient experienced Behavior Using Lisdexamfetamine Dimesylate an underlying mild depressive disorder, such “wear off I0123. The patient is a non-geriatric adult diagnosed with a effects correlated with worsening of an already mildly history of ADHD, inattentive type, and comorbid Generalized depressed mood, further lowered overall energy level, even Anxiety Disorder, though had no prior treatment. Presenting poorer concentration and unsettled sleep. The patient also ADHD symptoms included difficulty sustaining attention and indicated binging behavior in the evenings, typically charac attending to details, difficulty organizing tasks with tenden terized by rapidly devouring large amounts of “sweet' foods, cies toward avoidance, distractibility, and problems finishing while alone, and until feeling bloated. While the patient tasks that have been initiated. Symptoms of Generalized struggled with binging behavior for the past two decades, the Anxiety Disorder included frequent and intense ruminative US 2013/0045979 A1 Feb. 21, 2013 worrying, feeling overly fatigued, muscle tension and inter would typically lead to excess consumption of carbohydrate mittent problems with sleep. History suggests that a perse based foods. In recent years, the patient reported having Verative pattern of thinking and compulsive worrying may gained over 10% body weight and noted a general trend have evolved from deficits in attention and information pro toward increasing emotional eating and binging behavior. cessing. The patient was started on VYVANSE 30 mg in the More severe binges occurred at least several times per month morning, along with TRAZODONE 50 mg at bedtime. over a stretch of several years, though were much less com VYVANSE was maintained at 30 mg once daily in the morn mon than ‘emotional eating that was milder in nature and ing for one week, followed by one week at 50 mg per day, and occurred nearly daily. Medication treatment was initiated then 70 mg per day, taken in the morning. The patient expe with VYVANSE at 30 mg per day for two weeks and the dose rienced a positive effect across all ADHD and Generalized was increased to 50 mg per day, without any adverse effects. Anxiety Disorder symptoms within the first week, with more The patient was maintained on VYVANSE for 10 weeks at 50 dramatic improvement as the dose of VYVANSE was mg per day. The patient reported a rather abrupt and Sustained increased. The patient maintained treatment on VYVANSE at cessation of emotional eating behavior in the afternoon while 70 mg perday for 10 weeks; TRAZODONE 50mg at bedtime taking 50 mg VYVANSE daily. Symptoms of emotional eat was discontinued after 4 weeks as sleep patterns had suffi ing were improved in the evenings as well, with less than one ciently normalized. While maintained on VYVANSE at 70 per week on average as compared to most evenings previ mg per day, the patient noted significantly enhanced ability to ously. There were no reported major binges reported at any Sustain attention and attend to details, organize and finish point while taking VYVANSE and the patient lost approxi projects, and process information as compared to previous mately 6-7 pounds over 2/2 months of treatment. The patient baseline function, with clear and evident improvements in also noted significant amelioration of depressive symptoms, work function. The patient found, Surprisingly, a highly sig offeeling chronically low, and felt sufficiently motivated and nificant improvement on compulsive ruminating and worry invested in work and Social activities in a way that was not ing. The patient previously felt little or no control around such present for some time. The organization and execution of worrying, ruminative behavior and speculated that it caused work-related tasks improved during the course of treatment as significant mental and even physical fatigue. After 10 weeks well. of treatment with VYVANSE at 70 mg per day, the patient 0.126 The case report demonstrates successful treatment reported being only mildly affected by inattention symptoms of a comorbid depressive disorder (both major depressive and preoccupied primarily with realistic kinds of worries disorder and dysthymic disorder) and binge-eating behavior that were generally well-managed. with the amphetamine prodrug lisdexamfetamine dimesylate. 0.124. This case demonstrates the use of an amphetamine The patient also began a trend of weight loss on account of prodrug lisdexamfetamine dimeSylate as monotherapy for decreased emotional eating and binging. The patient’s ADHD comorbid ADHD and anxiety spectrum symptoms, most was also clinically relevant, which is the primary reason notably generalized anxiety (in this case Generalized Anxiety VYVANSE was chosen as the initial medication treatment, Disorder) that took on a perseverative and compulsive wor though it was not the reason for which evaluation and treat rying quality along with physical symptoms of fatigue and ment was sought and of secondary importance with regard to muscle tension. Stimulant medications have traditionally symptoms causing the patient difficulty and concern. Clinical been associated with causing or worsening anxiety symptoms improvement on depressive symptoms was present, most (for instance, being anxiogenic). It is thus Surprising that an notably improved interest in daily activities and overall amphetamine prodrug proved useful for treating the Gener mood. Binge-eating behavior, largely taking the form of self alized Anxiety Disorder symptoms for the duration of the day, Soothing eating activity with potentially serious risks in this with no problematic wear off. patient insofar as it was causing steady increased weight gain to the point of obesity), responded remarkably well to treat Example 4 ment with VYVANSE. The patient’s symptoms of ADHD, inattentive type, also demonstrated improvement and Treatment of Patient with Comorbid Depressive enhanced an overall sense of improved well being, effective Disorders and Binge Eating Behavior with ness, and confidence. Lisdexamfetamine Dimesylate Example 5 0.125. The patient is a non-geriatric adult with a history of intermittent major depressive disorder, dysthymic disorder, and binge eating behavior. The patient also endorsed symp Treatment of Binge Eating Disorder, toms of ADHD, inattentive type, primarily around problems Medication-Induced Cognitive Problems, and with organizing tasks, procrastination of work activities, and Fatigue with Lisdexamfetamine Dimesylate problems completing projects, though Such inattention I0127. The patient is a non-geriatric adult with a history of symptoms were considered as clinically less detrimental than recurrent major depressive disorder with comorbid anxiety feeling chronically depressed, lacking motivation or interest symptoms and severe binge eating disorder. The patient pre in work or Social activities, feeling fatigued and sometimes viously has been treated with therapy and has had multiple guilty, and having gained weight over several years due to prior medication trials, either discontinued due to lack of emotional eating behavior. The patient had received therapy efficacy or side effects, including ZOLOFT (sertraline), CEL in the past to address depressive episodes and associated life EXA (citalopram), PROZAC (fluoxetine), LEXAPRO (esci stressors, with modest benefit. The patient also described a talopram), WELLBUTRINSR (bupropion HCl), NORTRIP history of emotional eating that could occur at any time of TYLINE, ATIVAN (lorazepam), ABILIFY (aripiprazole), day though more often in the late afternoons or early eve RISPERDAL (risperidone), SEROQUEL (quetiapine), nings. Such emotional eating was often triggered by stress LYRICA (pregabalin), and RITALIN (methylphenidate). ful situations or events, accompanied by an urge to eat, and Selective serotonin reuptake inhibitors exacerbated binge eat US 2013/0045979 A1 Feb. 21, 2013 ing symptoms and caused problematic weight gain. For treat forgetfulness, and feeling poorly engaged. However, after ment of depression with comorbid anxiety, binge-eating, and beginning a new job with more challenging responsibilities, weight-gain related to binge eating symptoms, the patient was the patient was unable to compensate for Such deficits and a maintained on a medication regimen that included pattern of obsessive ruminations emerged, often involving TOPAMAX (topiramate) 175 mg in the morning and 200 mg work. In addition to perseverative and obsessive thinking, the at night, LAMICTAL (lamotrigine) 200 mg in the morning, patient experienced heightened anxiety and mild depressive CYTOMEL (liothyronine) 25 mcg per day, KLONOPIN symptoms, including fatigue, low mood, and amotivation, (clonazepam) 0.25 mg at bedtime, and NEURONTIN (gaba especially while at work. After discussing medication options pentin) 600 mg at bedtime. However, symptoms of depressed and side effect concerns, VYVANSE was initiated to address mood, hopelessness, amotivation, problems with concentra underlying ADHD symptoms, which were felt to drive the tion (possibly worsened with the use of TOPAMAX though patient's perseverative thinking, anxious ruminations, and prior attempts to decrease the dose exacerbated binge-eating low mood. VYVANSE was initiated at 30 mg per day for one symptoms), significant fatigue, and tendency toward emo week, and then titrated to 50 mg per day, without adverse tional eating and binging significantly increased from base effect. PAXIL was maintained at 30 mg per day. Over the line. Given prior poor response to a number of different course of the ensuing 9 weeks, the patient reported improve classes of medication trials, off-label use of VYVANSE was ment across ADHD, Generalized Anxiety Disorder, and initiated at 30 mg each morning to target a constellation of Major Depressive Disorder symptoms. Work function began symptoms, including symptoms of major depression, binge to feel easier, with better ability to attend to tasks and more eating disorder, fatigue, and concentration problems. efficient performance, improved attention to detail, and feel VYVANSE was maintained at 30 mg each morning for 5 ing internally less restless. The patient reported a substantial weeks before being discontinued due to adverse effects. reduction in worrying, an approximate 4-5% weight loss over These side effects were excessive appetite Suppression and 2 months of treatment, and improved mood, motivation and visual blurring. However, during the time of treatment, the energy. patient indicated a notably reduced urge to binge, fewer abso 0.130. The case report exemplifies the use of the amphet lute binges per week, fewer binge-eating days per week, and amine prodrug lisdexamfetamine dimesylate to address mul improvement in both fatigue and concentration throughout tiple clinical issues, the most unexpected one being the alle the day. However, there appeared to be no benefit on the viation in generalized anxiety symptoms, perseverative patient’s depressed mood, amotivation, and feelings of hope thinking, and obsessive ruminations. The patients initial pre lessness. senting symptoms in past treatment have been within the class 0128. This case exemplifies the clinical benefit of lisdex of Anxiety Disorders, mainly of Generalized Anxiety Disor amfetamine dimeSylate on binge-eating symptoms and der but also possibly Obsessive-Compulsive Disorder, as well potentially on weight-gain related to binging (body weight as within the class of Depressive Disorders, mainly Major was not obtained), though longer-term treatment was cut Depressive Disorder. While the patient may have exhibited short by adverse effects at the 30 mg dosage form. Given the ADHD symptoms in the past, they were considered clinically number of failed prior trials, off-label use of VYVANSE was of a secondary nature. Such that pharmacologic treatment had clinically indicated, especially given the severity of binge been initiated with the selective serotonin reuptake inhibitor eating behavior. Though TOPAMAX helped reduce binge (SSRI) PAXIL (paroxetine) to target both depressive and eating behavior, it was clinically insufficient to fully address anxiety spectrum symptoms. The use of the amphetamine binge eating behavior, as it was poorly tolerated at higher prodrug VYVANSE was able to accomplish a number of doses due to cognitive side effects, and may have had a clinically very important objectives, with full-day duration contributory role in cognitive slowing and fatigue at the main effects, including augmentation of the mood-enhancing tenance dose. effect of the antidepressant PAXIL, alleviation of anxiety spectrum symptoms (including worrying and obsessive/com Example 6 pulsive mental behavior), and reduction of ADHD symptoms. 1. (canceled) Treatment of a Patient with Comorbid Generalized 2. A method of treating major depressive disorder compris Anxiety Disorder, Major Depression, and ADHD ing (i) diagnosing a patient as having major depressive disor with Lisdexamfetamine Dimesylate der and as failing to achieve remission in response to antide 0129. Patient 6 is a non-geriatric adult with a history of pressant therapy and (ii) administering to the patient an Generalized Anxiety Disorder and Major Depressive Disor effective amount lisdexamfetamine dimesylate together with der. The patient was maintained on PAXIL (paroxetine) 30 an additional active agent, wherein the additional active agent mg per day following a significant comorbid major depres is an antidepressant, and the effective amount is an amount sive episode associated with anxiety symptoms, and a history effective in a clinical trial of efficac of lisdexamfetamine consistent with Generalized Anxiety Disorder. Treatment dimes late for treating major depressive disorder, in which with PAXIL had rapidly stabilized both depressive and anxi data is submitted to the FDA. ety symptoms and for approximately 2 years the patient was 3-5. (canceled) maintained at 30 mg per day with no change in dose. Over this 6. The method of claim 2 wherein from 2.5 to 200 mg time, the patient had gained approximately 10% of their body lisdexamfetamine dimesylate is administered daily. weight. It was periodically addressed that the patient may 7. The method of claim 2, wherein 15 to 100 mg lisdexam have experienced previous academic difficulties due to fetamine dimesylate is administered once per day. ADHD, inattentive type, though during the course of treat 8. (canceled) ment with PAXIL, the patient was generally able to adapt to 9. The method of claim 2, wherein the effective amount is work pressures and developed compensatory strategies to additionally an amount effective to decrease major depressive deal with organizational difficulties, auditory inattention and disorder symptoms. US 2013/0045979 A1 Feb. 21, 2013

10. The method of claim 9, wherein the decrease in major amibegron, casopitant, delucemine, elzasonan, gepirone, depressive disorder symptoms is a 50% or greater reduction mecamylamine, milnacipran, miraxion, nemifitide, pexacer of symptoms identified on a depression symptom rating scale font, Saredutant, tofisopam, Vestipitant, VilaZodone, aripipra or achieving a score less than or equal to 7 on the HRSD; or Zole, clozapine, loxapine, olanzapine, paliperidone, quetiap less than or equal to 5 on the QIDS-SR: or less than or equal ine, risperidone, Sertindole, Ziprasidone, asenapine, to 10 on the MADRS. iloperidonepimavanserin, lithium, Valproic acid, carbam 11. The method of claim 2, wherein the additional active azepine, eslicarbazepine, lamotrigine, levetiracetam, oXcar agent is an antidepressant selected from a selective serotonin baZepine, tiagabine, topiramate, vigabatrin, Zonisamide, rilu reuptake inhibitor, a serotonin 5HT receptor partial agonist or Zole, Varenicline, L or pharmaceutically active salts or antagonist, a norepinephrine dopamine reuptake inhibitor, a prodrugs thereof, or a combination of the foregoing. serotonin norepinephrine dopamine reuptake inhibitor, a 13. (canceled) selective serotonin norepinephrine reuptake inhibitor, a sero 14. The methods of claim 52, wherein the additional active tonin 5-HT1a partial agonist, a serotonin 5-HT1b agonist, a agent an antidepressant chosen from mirtazapine, escitalo serotonin 5-HT2 antagonist, a serotonin 5-HT6 antagonist, a pram, fluoxetine, Sertraline, citalopram, bupropion, Venlafax serotonin-2 antagonist reuptake inhibitor, a serotonin-1 ago ine, dulloxetine, and the pharmaceutically acceptable salts and nist reuptake inhibitor, a mixed serotonin antagonist reuptake hydrates of any of the foregoing. inhibitor/partial agonist/dopamine agonist, an alpha-2 15-16. (canceled) antagonist/serotonin 5HT2-3 receptor antagonist, a serotonin 17. A method of using lisdexamfetamine dimesylate com modulator or stimulator, a mixed serotonin antagonist/mela prising informing a user that the lisdexamfetamine dismesy tonin agonist, a mixed serotonin dopamine antagonist, a tri late may be used to treat major depressive disorder. cyclic antidepressant, a tetracyclic antidepressant, a bis-aryl 18. The method of claim 17 additionally comprising pro Sulphanyl modulator, a beta-3 adrenoreceptor stimulator or viding the user with an amount of lisdexamfetamine dimesy agonist, a beta-3 adrenoreceptor antagonist, a nicotinic ace late effective in a clinical trial of efficacy of lisdexamfetamine tylcholine receptor agonist or antagonist, an enkephalinergic dimesylated for treating major depressive disorder, in which modulator, an aprepitant, a neurokinin (NK) antagonist, a data is submitted to the FDA. NK1, 2, or 3 antagonist, a neuropeptide (NP)Yantagonist, a 19. The method of claim 18, additionally comprising pro NPY1, 2, or 3, or 5 antagonist, a substance Pantagonist, a viding lisdexamfetamine dimesylate in a container and the corticotrophin-releasing hormone (CRH or CRF) antagonist, informing is by reference to a package insert associated with a CRH (or CRF)-1 antagonist, a glucocorticoid receptorago the container. nist or partial agonist, a glucocorticoid receptor antagonist, a 20. The method of claim 17, wherein the informing is by glucocorticoid receptor type II antagonist, an anti-convul reference to information material; by reference to a package sant, a glutamate modulator, an mGluR receptor modulator, active agent insert, a flyer or an advertisement; by presenta agonist or antagonist, an mGluR2/3 agonist, an mGluR5 tion of information at a seminar, conference, or other educa antagonist, an estrogen receptoragonist orantagonist, a mela tional presentation; or by a conversation between a pharma tonin receptor agonist or antagonist, a glycine transporter ceutical sales representative and a medical care worker. inhibitor, an alpha-1 receptor agonist, an alpha-1 receptor 21-26. (canceled) antagonist, an alpha-2 receptor agonist, an alpha-2 receptor 27. A method of using lisdexamfetamine dimesylate com antagonist, a vasopressin-1B (V1B) agonist orantagonist, an prising (i) conducting a clinical trial of the efficacy lisdexam NMDA modulator (i.e., a partial agonist, agonist, or antago fetamine dimeSylate for treating major depressive disorder nist), a mood modulating (i.e., stabilizing) agent, a monoam and (ii) informing a purchaser of the lisdexamfetamine dis ine oxidase inhibitor, or a combination of the foregoing. mesylate that the lisdexamfetamine dismesylate is efficacious 12. The method of claim 11, wherein the additional active for treating major depressive disorder. agent is clovoxamine, femoxetine, flesinoxan, citalopram, 28. (canceled) escitalopram, fluoxetine, fluvoxamine, paroxetine, Sertraline, 29. The method of claim 27, wherein the clinical trial dulloxetine, desvenlafaxine, mirtazapine, Venlafaxine, atom generates data that is submitted to the FDA. oxetine, reboxetine, thionisoxetine, bupropion, mianserin, 30. The method of claim 2, wherein the amphetamine nefazodone, traZodone, doxepin, amitriptyline, amoxapine, prodrug, methylphenidate prodrug, or methylphenidate ana clomipramine, desipramine, doxepin, imipramine, mapro log is lisdexamfetamine and 15 to 75 mg lisdexamfetamine tiline, nortriptyline, protriptyline, trimipramine, tranyl are administered daily. cypromine, isocarboxazid, phenelzine, selegiline, moclobe mide, buspirone, tryptophan, pindolol, agomelatine, k k k k k