US 20100166889A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0166889 A1 Sanfilippo (43) Pub. Date: Jul. 1, 2010

(54) METHOD OF TREATING DEPRESSIVE A63/495 (2006.01) DSORDERS A 6LX 3/553 (2006.01) A 6LX 3/59 (2006.01) (75) Inventor: Louis Sanfilippo, New Haven, CT A63L/454 (2006.01) (US) A6II 3/445 (2006.01) A6II 3/19 (2006.01) Correspondence Address: A6II 3/405 (2006.01) CANTOR COLBURN, LLP A63L/4525 (2006.01) 20 Church Street, 22nd Floor A63L/35 (2006.01) Hartford, CT 06103 (US) A 6LX 3L/95 (2006.01) A6II 3/423 (2006.01) (73) Assignee: LCS GROUP, LLC, New Haven, A6II 3/428 (2006.01) CT (US) A6IP 25/24 (2006.01) (21) Appl. No.: 12/646,441 G06O 90/00 (2006.01) (52) U.S. Cl. ... 424/722: 514/626; 514/317: 514/254.11: (22) Filed: Dec. 23, 2009 514/469: 514/438: 514/214.02: 514/239.2: 514/254.05; 514/450; 514/211.13: 514/217; Related U.S. Application Data 514/378; 514/252.15; 514/419:514/415; 514/253.13: 514/407: 514/252.18; 514/620; (63) Continuation of application No. 12/666,460, filed as 514/245; 514/221; 514/331; 514/255.01; application No. PCT/US08/01002 on Jan. 24, 2008. 514/254.09:514/253.07: 514/220; 514/259.41: (60) Provisional application No. 60/972,046, filed on Sep. 514/323: 514/321; 514/329; 514/557: 514/242: 13, 2007. 514/424; 514/326; 514/455; 514/561; 514/379; 514/367; 514/215; 705/500 Publication Classification (57) ABSTRACT (51) Int. Cl. A6 IK33/00 (2006.01) The invention provides methods of treating depressive disor A6 IK3I/I65 (2006.01) ders, in particular major depression but other depressive A6 IK 3L/45 (2006.01) orders also, with prodrug stimulants or analogs including A6 IK 3/496 (2006.01) amphetamine prodrugs, methylphenidate prodrugs, and A6 IK3I/343 (2006.01) methylphenidate analogs. Such methods of treatment may A6 IK3I/38 (2006.01) utilize the prodrug stimulant or analog as monotherapy or, A6 IK3I/55 (2006.01) more commonly, as an adjunct to antidepressant medication A 6LX 3/5.375 (2006.01) treatment to augment their effect. The invention includes A6 IK3I/335 (2006.01) combination methods of treatment in which an amphetamine A 6LX 3/553 (2006.01) prodrug, methylphenidate prodrug, or methylphenidate ana A6 IK 3/42 (2006.01) log is administered to an individual in need with one or more A6 IK3I/506 (2006.01) other active agents, either in separate forms or as a single A6 IK 3/405 (2006.01) pharmaceutical formulation. Packaged pharmaceutical com A6 IK 3/404 (2006.01) positions containing an amphetamine or methylphenidate A6 IK 3L/45 (2006.01) prodrug, instructions for using the prodrug to treat certain A6 IK3I/53 (2006.01) disorders, and optionally one or more other active agents are A6 IK3I/55 (2006.01) provided by the invention. US 2010/0166889 A1 Jul. 1, 2010

METHOD OF TREATING DEPRESSIVE behaviors and weight gain may be a direct effect of Such DISORDERS medication(s). Psychotropic medications may also exacer bate an underlying binge eating disorder in Some patients. FIELD OF INVENTION 0005 Medical complications associated with binge eating 0001. The inventor has discovered that amphetamine pro disorder include high blood pressure, high cholesterol and drugs and methylphenidate prodrugs are useful for treating a triglycerides, kidney disease (and failure), gallbladder dis number of central nervous system disorders. Methods of ease, arthritis, bone deterioration, stroke, upper respiratory treating binge eating disorders, obesity resulting from binge infections, skin disorders, menstrual irregularities, ovarian eating behavior, and depression are included herein. The abnormalities, and pregnancy complications. Psychiatric invention includes methods of treating certain co-morbidities problems associated with, or exacerbated by, binge eating in ADHD (Attention-Deficit Hyperactivity Disorder) and disorder include depressive disorders, mood disorders, anxi ADD patients; for example the invention includes methods of ety disorders, ADHD and ADD, personality disorders, other treating generalized anxiety disorder, obsessional and rumi eating disorders, Suicidal thoughts, and Substance abuse dis native thought disorders, and obsessive/compulsive behavior orders. in ADHD and ADD patients. Methods of treatment include 0006 Individuals with binge eating disorder may respond methods in which the amphetamine prodrug, methylpheni to treatment with antidepressants, though Such medications date prodrug, or methylphenidate analog is the only active may contribute to a worsening of binge eating symptoms, agent. The invention also includes combination methods of along with weight gain, either at the outset of treatment or treatment in which an amphetamine prodrug, methylpheni over time. date prodrug, or methylphenidate analog is administered with Depression one or more other active agents. Methods of use described herein include informing a user that an amphetamine prodrug, 0007 Depression is often difficult to treat, as some methylphenidate prodrug, or methylphenidate analog may be patients fail to respond to an initial pharmacologic interven used to treat any of the disorders listed above. The invention tion and a decision must be made to Switch agents, augment includes pharmaceutical compositions comprising an with another medication(s), or combine multiple pharmaco amphetamine prodrug, methylphenidate prodrug, or meth logic agents. Combining medications, while often helpful, ylphenidate analog together with one or more other active can sometimes be problematic with added side effect bur agents in a single dosage form. Packaged pharmaceutical dens. Side effects of certain psychotropic medication some compositions containing an amphetamine prodrug, meth times used to offer adjunct treatment to patients already tak ylphenidate prodrug, or methylphenidate analog with instruc ing antidepressants may include weight gain and obesity. tions for using the composition to treat one of the disorders 0008 Individuals treated for major depressive disorders listed above are also provided. may show a positive response or full remission of symptoms to medication treatment, though recent clinical evidence Sug BACKGROUND gests remission rates following an adequate course of mono therapy treatment may as low as 30-40%. Further, clinical Binge Eating Disorder and Obesity Resulting from studies suggest an unusually large percentage of depressed Binge Eating Disorder individuals treated with antidepressant medication, greater 0002 Binge Eating Disorder is a form of Eating Disorder than 30-40% in various clinical studies, show only a partial Not Otherwise Specified according the Diagnostic and Sta response (for example, full remission is not achieved but there tistical Manual of Mental Disorders (DSM-IV-TR). As is some measure of improvement in depressive symptoms). defined by the DSM-IV-TR, it is characterized by recurrent Some patients may be refractory or resistant to treatment binge eating episodes. and fail to respond to one, or in Some cases, multiple mono 0003 Commonly described symptoms of binge eating therapy and combination antidepressant medication treat disorder include frequent dieting and weight loss, hoarding of mentS. food, hiding empty food containers, eating late at night, attri 0009 Major depressive disorders similarly may lead to bution of one's Successes and failures to weight, avoiding deteriorating physical health and may increase the risk of Social situations where food may be present, and feeling morbidity and mortality in patients with concurrent medical depressed or anxious. Binge eating also may cause rapid and conditions. unhealthy weight gain (or loss), weight fluctuations, and 0010. Similarly, depressive disorders are often associated chronic erratic eating behavior. Binge eating disorder and with, or may exacerbate, other mood disorders, anxiety dis symptoms associated with binge eating disorder may result in orders, attention deficit hyperactivity disorder (ADHD or obesity though obesity is not necessarily a result of binge ADD), psychotic disorders, personality disorders, eating dis eating disorder. Further, patients with binge eating disorder orders, cognition and cognitive disorders, Substance abuse are often not obese and may even have a below normal disorders, and Suicidal ideation. weight. 0011. There exists an unmet and important clinical need 0004. The biological basis of binge eating disorder is for treatments for binge eating disorders, obesity resulting poorly understood. Binge eating disorder is difficult to treat from binge eating behavior, and depression that is only par and carries significant medical and psychiatric risks. Pharma tially responsive to medication and intractable (e.g. treat cologic interventions have been of limited Success and some ment-resistant) depression. The present invention fulfills this times cause a worsening of binge eating symptoms. A number need and provides additional advantages described herein. of psychotropic medications, including but not limited to antidepressants, antipsychotics, antimanic agents, and mood SUMMARY OF THE INVENTION modulating medications are known to cause binge eating, 0012. The inventor has discovered that amphetamine pro dysregulation of appetite, and weight gain. Binge eating drugs, including lisdexamfetamine dimesylate, methylpheni US 2010/0166889 A1 Jul. 1, 2010

date prodrugs, and certain methylphenidate analogs, are use includes (i) lisdexamfetamine dimeSylate and (ii) one or more ful for treating binge eating disorders, obesity resulting from other active agent(s) combined in a single dosage form. binge eating behavior, and depression. Furthermore amphet 0018. The invention includes articles of manufacture com amine prodrugs, methylphenidate prodrugs, and certain prising an amphetamine prodrug, methylphenidate prodrug, methylphenidate analogs have been found useful for treating or methylphenidate analog in a container and printed label certain co-morbidities in ADHD and ADD patients. The ing. The printed labeling states that the amphetamine pro invention includes methods of treating generalized anxiety drug, methylphenidate prodrug, or methylphenidate analog is disorder, obsessional and ruminative thought disorders, and useful for treating a binge eating disorder, obesity resulting obsessive/compulsive behavior in patients, particularly in from binge eating behavior, or depression. In other embodi ADHD/ADD patients. Methods of using amphetamine pro ments the printed labeling states that the amphetamine pro drugs, methylphenidate prodrugs, or methylphenidate ana drug, methylphenidate prodrug, methylphenidate analog is 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. 0013 The invention includes a method of treating binge eating disorder or obesity resulting from binge eating behav ior, comprising diagnosing a patient as having a binge eating DETAILED DESCRIPTION disorder or obesity resulting from binge eating behavior and Terminology providing an effective amount of amphetamine prodrug, methylphenidate prodrug, or methylphenidate analog to the 0019 Prior to setting forth the invention in detail, it may be patient. helpful to provide definitions of certain terms to be used herein. Compounds of the present invention are described 0014. 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. 0020. The terms “a” and “an do not denote a limitation of 0015 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 0021. 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 0016. 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 0017. 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 0022 "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 US 2010/0166889 A1 Jul. 1, 2010

the DSM-IV-TR, binge eating disorders are associated with 17-Item Hamilton Rating Scale of Depression (HRSD7), the three or more of the following symptoms: eating until uncom 30-Item Inventory of Depressive Symptomatology (IDS 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 0027 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 0023 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 (0028 “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 0024 Depressive symptoms or features such as low mood, of the anxiety typically manifests in the following manner: diminished interest in activities, psychomotor slowing oragi 0029 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 0030) 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 0031 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 0032. 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 0025. 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) 0033 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 0034) "Obsessive behavior” may arise in many different not due to a general medical or Substance abuse condition. clinical forms, including recurrent thoughts, impulses or 0026 “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 interne compulsions, and compulsive exercising US 2010/0166889 A1 Jul. 1, 2010

or lying. The Yale-Brown Obsessive Compulsive Scale 0041. A “medical care worker” means any worker in the (Y-BOCS) is often used to assess symptom severity for health care field who may need information regarding an 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, physician's 0035 “Obesity” is defined as a BMI (Body Mass Index) assistants, nurses, caretakers, emergency medical workers, >30 (kg/m). and Veterinarians. 0036 “Efficacy” means the ability of an active agent administered to a patient to produce a therapeutic benefit in 0042. A "patient’ means any human or non-human animal the patient. in need of medical treatment. Medical treatment can include 0037. The terms "amphetamine prodrug and “meth treatment of an existing condition, such as a disease or disor ylphenidate prodrug” refer to any product that contains either der, prophylactic or preventative treatment, or diagnostic an amphetamine (CAS Reg. No. 300-62-9) or methylpheni treatment. In some embodiments the patient is a human date (CAS Reg. No. 113-45-1) compound conjugated to a patient. chemical moiety such that the conjugated amphetamine or 0043. As used herein “a pharmaceutical supplier means methylphenidate must undergo a conversion in a patient's any person (other than a medical care worker), business, body to become the active amphetamine or methylphenidate charitable organization, governmental organization, or other form. Amphetamine' includes dextro and levo amphetamine entity involved in the transfer of active agent between entities, forms and all pharmaceutically acceptable amphetamine for profit or not. Examples of pharmaceutical Suppliers salts. Conversion typically involves metabolism. “Meth include pharmaceutical distributors, pharmacies (online or ylphenidate' also includes all methylphenidate optical iso physical), foreign businesses or individuals importing active mers and all pharmaceutically acceptably methylphenidate agent into the United States, the hospitals, HMOs and the salts. For example “methylphenidate includes pure dexm Veterans Administration. ethylphenidate (a-phenyl-2-piperidineacetatehydrochloride, 0044) “Pharmaceutically acceptable salts' includes (R,R)-(+)-) and racemic mixtures of d- and 1-methylpheni derivatives of the disclosed compounds, wherein the parent date forms. compound is modified by making non-toxic acid or base 0038 Lisdexamfetamine dimesylate, CAS Reg. No. addition salts thereof, and further refers to pharmaceutically 608137-32-3, (2S)-2,6-diamino-N-(1S)-1-methyl-2-phe acceptable solvates, including hydrates, of Such compounds nylethyl hexanamide dimethanesulfonate, is an amphet and Such salts. Examples of pharmaceutically acceptable amine prodrug in which L-lysine is covalently bound to d-am salts include, but are not limited to, mineral or organic acid phetamine. Lisdexamfetamine dimeSylate is sold under the addition salts of basic residues such as amines; alkali or trade name VYVANSE (Shire). It has the chemical formula: organic addition salts of acidic residues such as carboxylic acids; and the like, and combinations comprising one or more of the foregoing salts. The pharmaceutically acceptable salts NH include non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic NH2 inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids such as hydro chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal \M/ salts such as sodium salt, potassium salt, cesium salt, and the 1 No like; and alkaline earth metal salts, such as calcium salt, 2 . magnesium salt, and the like, and combinations comprising one or more of the foregoing salts. "Lisdexamfetamine' is typically administered as a dimesy 0045 Pharmaceutically acceptable organic salts include late salt but includes all pharmaceutically acceptable salts of salts prepared from organic acids such as acetic, trifluoroace lisdexamfetamine free base. The term “lisdexamfetamine' tic, propionic. Succinic, glycolic, Stearic, lactic, malic, tar also encompasses all polymorphs and hydrates of this drug. taric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe 0039) “Informing in any of the above embodiments of the nylacetic, glutamic, benzoic, salicylic, mesylic, esylic, invention may occur by reference to, or providing, informa besylic, Sulfanilic, 2-acetoxybenzoic, fumaric, toluene tion material. Informing can also occur by presentation at a Sulfonic, methanesulfonic, ethane disulfonic, oxalic, seminar, conference, or other educational presentation; or by isethionic, HOOC-(CH), COOH where n is 0-4, and the providing an active agent with informational material to a like; organic amine salts such as triethylamine salt, pyridine user, or in a conversation between a pharmaceutical sales salt, picoline salt, ethanolamine salt, triethanolamine salt, representative and a medical care worker or between a medi dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, cal care worker and a patient. and the like; and amino acid salts such as arginate, aspargin 0040 “Informational material' means any media provid ate, glutamate, and the like, and combinations comprising one ing information. Media includes printed, audio, visual, or or more of the foregoing salts. electronic media. Examples of information material are flyer, 0046 “Providing includes giving, selling, distributing, an advertisement, a package insert for a pharmaceutical prod transferring (for profit or not), manufacturing, compounding uct, printed labeling, an internet web site, an internet web or dispensing. page, an internet pop-up window, or information recorded on 0047. A "product' or “pharmaceutical product' is a dos a compact disk, DVD, an audio recording, or any other age form of an active agent plus published material and recording or electronic medium. optionally packing. US 2010/0166889 A1 Jul. 1, 2010

0048 “Safety” means the incidence of adverse events 0054 The arrow indicates a chemically accessible site at associated with administration of an active agent, including which labile groups may be added to create methylphenidate adverse effects associated with patient-related factors (e.g., prodrugs. Amino acid methylphenidate prodrugs may be pre 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 0049. 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 0055 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 Student's 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. 0050. A “user' is a patient, a medical care worker, or a Methylphenidate Analogs pharmaceutical Supplier. 0056 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 0051 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

0.052 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 0053 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 0057 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 US 2010/0166889 A1 Jul. 1, 2010 obsessive/compulsive behavior in patients, particularly in in depressive and binge eating disorders. Such a profile is ADHD and ADD patients. The amphetamine prodrug, meth particularly significant for depressive disorders, where a low ylphenidate prodrug, or methylphenidate analog may be the mood is characteristically present through the entire day and 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 0058. 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 anti-depressant medications. have some relation to feelings of dysphoria as other stimulant 0059. 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 0065 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 0060. 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 0.066 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 0061. 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 0062 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. 0063. While amphetamine and methylphenidate based 0067 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 0068. 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 0064. 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 0069. 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 0070 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 US 2010/0166889 A1 Jul. 1, 2010 mood disorders may actually contribute to weight gain, obe 0073 Frequency of dosage may vary depending on the sity, or increased abdominal girth, with potentially untoward compound used and the particular condition or disorder to be psychological effects or medical sequelae Such as hypertrig treated or prevented. For most disorders a dosage regimen of 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 0071. 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 0074. 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 0075. 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. 0072 The invention further includes methods of using 0076. 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 0077. 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 0078. 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 US 2010/0166889 A1 Jul. 1, 2010 reuptake inhibitor, a serotonin-1 agonist reuptake inhibitor, a I0087 Serotonin-2 antagonist reuptake inhibitors include, mixed serotoninantagonist reuptake inhibitor/partial agonist/ but are not limited to, trazodone. dopamine agonist, an alpha-2 antagonist/serotonin 5HT2-3 I0088 Alpha-2 antagonist/serotonin 5HT2-3 receptor receptor antagonist, a serotonin modulator or stimulator, a antagonists include, but are not limited to, mirtazapine. mixed serotonin antagonist/melatonin agonist, a mixed sero I0089. Norepinephrine dopamine reuptake inhibitors tonin dopamine antagonist, a tricyclic antidepressant, a tetra include, but are not limited to bupropion. cyclic antidepressant, a bis-aryl-Sulphanyl modulator, a 0090 Tricyclic antidepressants include, but are not lim beta-3 adrenoreceptor stimulator or agonist, a beta-3 adreno ited to, doxepin, amitriptyline, amoxapine, clomipramine, receptorantagonist, a nicotinic acetylcholine receptoragonist desipramine, doxepin, imipramine, maprotiline, nortrip or antagonist, an enkephalinergic modulator, an aprepitant, a tyline, protriptyline, and trimipramine. neurokinin (NK) antagonist, a NK1, 2, or 3 antagonist, a 0091 Benzodiazepines include but are not limited to, neuropeptide (NP)Yantagonist, a NPY1, 2, or 3, or 5 antago alprazolam, clonazepam, diazepam, lorazepam, flurazepam, nist, a Substance Pantagonist, a corticotrophin-releasing hor and bentazepam. mone (CRH or CRF) antagonist, a CRH (or CRF)-1 antago 0092 Anti-manics include, but are not limited to, carbam nist, a glucocorticoid receptor agonist or partial agonist, a azepine, Valproic acid and lithium. glucocorticoid receptor antagonist, a glucocorticoid receptor 0093 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 0094 Wakefulness promoting agents include but are not antagonist, a GABA channel antagonist, a GABA reuptake limited to modafinil and armodafinil. inhibitor, a glutamate modulator, an mGluR receptor modu 0.095 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 0096 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 0097. 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 0.098 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, 0099. 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 0079 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) 0080 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 0081 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; 0082 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. 0100. An anti-diabetes agent may include a glucose-low 0083. Selective serotonin reuptake inhibitors include, but ering (i.e., hypoglycemic) agent; an alpha-glucosidase inhibi are not limited to, citalopram, escitalopram, femoxetine, flu tor; an amylin analog; a biguanide; an incretin mimetic or oxetine, fluvoxamine, paroxetine, Sertraline, and Zimeldine. analog; a glucagon-like peptide-1 (GLP-1) agonist or analog: 0084. Serotonin partial agonists include, but are not lim a dipeptidyl peptidase (DPP) inhibitor; a DPP-IV inhibitor; a ited to, pindolol, gepirone, and flesinoxan. glucose-dependent insulinotropic peptide (GIP) agonist or 0085. Selective serotonin norepinephrine reuptake inhibi analog; a gastric inhibitory peptide analog; a form of insulin tors include, but are not limited to, dulloxetine, Venlafaxine, (ie, injectable or inhaled); a fructose 1.6 biphosphatase (FB desvenlafaxine, milnacipran, and clovoxamine. Pase) inhibitor; a meglitinide; a peroxysome proliferators I0086 Norepephrine reuptake inhibitors include, but are activated receptor (PPAR) modulator, agonist orantagonist; a not limited to, atomoxetine and reboxetine. PPAR-gamma agonist orantagonist; a protein-tyrosine phos US 2010/0166889 A1 Jul. 1, 2010 phatase (PTP) 1B modulator, agonist orantagonist; a sodium prises a label approved by a regulatory agency for the product. dependent glucose transporter (SGLT) inhibitor; a sulfony In certain embodiments the labeling is labeling approved by lurea; or a thiazolidinedione (ie, a 'glitaZone'). the United States FDA. 0101 The invention includes combination methods of 0105. An example of an article of manufacture provided treatment in which an amphetamine prodrug, Such as lisdex by the invention is a packaged pharmaceutical compositions amfetamine dimesylate, a methylphenidate prodrug, or a comprising an amphetamine prodrug, methylphenidate pro methylphenidate analog is provided together with a Norepi drug, or methylphenidate analog in a container and printed nephrine/Dopamine Reuptake Inhibitor, a Serotonin labeling stating that the amphetamine prodrug, methylpheni Reuptake Inhibitor, a Selective Serotonin Norepinephrine date prodrug, or methylphenidate analog is useful for treating Reuptake Inhibitor, a Norepinephrine Reuptake Inhibitor, or a binge eating disorder or associated symptoms, obesity an Anticonvulsant. For example the invention includes com resulting from binge eating behavior, or depression. bination methods in which the amphetamine prodrug (e.g. 0106 When an article of manufacture of this invention lisdexamfetamine dimeSylate) or methylphenidate prodrug is comprises lisdexamfetamine dimesylate, the labeling may advise administering 2.5 mg to 250 mg, 2.5 mg to 12.5 mg. provided in combination with one or more of bupropion HCl, 2.5 to 15 mg, 10 to 100 mg per day, 20 to 70 mg per day, or Venlafaxine, paroxetine, mirtazapine, dulloxetine, citalopram, about 50 mg per daylisdexamfetamine dimesylate. The label escitalopram, fluoxetine, Sertraline, atomoxetine, topiramate, ing may advise that lisdexamfetamine dimesylate is to be Zonisamide, lamotrigine, gabapentin, tiagabine, or pregaba administered once daily, but there may be clinical value in lin. Some patients for up to two times per day. 0102. When treating binge eating the following active agents are particularly useful in combination with a meth Pharmaceutical Preparations ylphenidate prodrug or amphetamine prodrug: orlistat, bupropion, memantine, naltrexone, acamprosate, topiramate, 0107 An amphetamine prodrug, methylphenidate pro Zonisamide, sibutramine. Sibutramine may not be suitable for drug, or methylphenidate analog alone or in combination with all patients because of its tendency to elevate pulse and blood one or more other active agent(s) can be administered as the neat chemical, but is preferably administered as a pharma pressure. Zonisamide is effective for treatment of binge eat ceutical composition or formulation. Accordingly, the inven ing but is not always well tolerated. tion provides pharmaceutical formulations comprising an 0103) When treating depression the following active amphetamine prodrug, methylphenidate prodrug, or meth agents are particularly useful in combination with a meth ylphenidate analog alone or in combination with one or more ylphenidate prodrug or amphetamine prodrug: excitalopram, other active agents together with one or more pharmaceuti Sertraline, fluoxetine, citalopram, bupropion, Venlafaxine, cally acceptable carriers. Pharmaceutical formulations com and duloxetine. prising lisdexamfetamine dimesylate have been previously described in U.S. Pat. No. 7,105,486, which is hereby incor Articles of Manufacture porated by reference at cols. 13 to 17 for its teachings regard 0104. The invention includes articles of manufacture, ing amphetamine prodrug formulations including lisdexam which comprise an amphetamine prodrug, methylphenidate fetamine dimesylate formulations. prodrug, or methylphenidate analog in a container and label 0108. An amphetamine prodrug, methylphenidate pro ing stating that the amphetamine prodrug, methylphenidate drug, or methylphenidate analog alone or in combination with prodrug, or methylphenidate analog is effective for treating one or more other active agent(s) may be administered orally, certain central nervous system disorders; including treating topically, parenterally, by inhalation or spray, Sublingually, binge eating disorders, obesity resulting from binge eating transdermally, via buccal administration, or by other means, behavior, and depression. The labeling may also state that the in dosage unit formulations containing conventional non amphetamine prodrug, methylphenidate prodrug, or meth toxic pharmaceutically acceptable carriers, excipients, adju ylphenidate analog is effective for treating certain co-mor vants, and vehicles. Oral dosages forms such as tablets, tro bidities in ADHD and ADD patients; for example the inven ches, lozenges, aqueous or oily Suspensions, dispersible tion includes methods of treating generalized anxiety powders or granules, emulsions, hard or soft capsules, or disorder, obsessional and ruminative thought disorders, and syrups or elixirs are preferred. Oral administration is pre obsessive/compulsive behavior in ADHD and ADD patients. ferred for lisdexamfetamine dimesylate administration. In The amphetamine prodrug, methylphenidate prodrug, or Some embodiments solid oral dosage forms are preferred. methylphenidate analog present in this article of manufacture Tablets, capsules, and inhalable (e.g. intranasal) preparations may be lisdexamfetamine dimeSylate or some other amphet are preferred. Compositions intended for oral use may be amine prodrug, methylphenidate prodrug, or methylpheni prepared according to any method known to the art for the date analog. The article of manufacture may comprise the manufacture of pharmaceutical compositions and Such com amphetamine prodrug, methylphenidate prodrug, or meth positions may contain one or more agents, such as Sweetening ylphenidate analog as the only active agent or may include agents, flavoring agents, coloring agents and preserving one or more additional active agents. Additional active agents agents, in order to provide pharmaceutically elegant and pal may be combined in a single dosage form with the amphet atable preparations. amine prodrug, methylphenidate prodrug, or methylpheni 0109 Oral formulations contain between 0.1 and 99%, at date analog or may be packaged as separate dosage forms. least about 5% (weight%), 25% to about 50% or from 5% to The article of manufacture may comprise packaging material 75% of an amphetamine prodrug, methylphenidate prodrug, and a dosage form of an amphetamine prodrug, methylpheni or methylphenidate analog alone or in combination with one date prodrug, or methylphenidate analog contained within the or more other active agent(s) and usually at least about 5% packaging material, wherein the packaging material com (weight%) of a compound of the present invention. US 2010/0166889 A1 Jul. 1, 2010

0110. In addition to the amphetamine prodrug, meth about 50 mg per day lisdexamfetamine dimeSylate together ylphenidate prodrug, or methylphenidate analog alone or in with one or more of microcrystalline cellulose, croScarmel combination with one or more other active agent(s), the com lose Sodium, and magnesium Stearate in a gelatin capsule. The positions of the invention may contain a pharmaceutically invention also includes methylphenidate tablets comprising acceptable carrier, one or more compatible solid or liquid 2.5 to 200 mg methylphenidate prodrug together with lactose, filler diluents or encapsulating Substances, which are Suitable magnesium Stearate, polyethylene glycol, starch, Sucrose, for administration to an animal. Carriers must be of suffi talc, and gum tragacanth. ciently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated. EXAMPLES The carrier can be inert or it can possess pharmaceutical 0115 The following examples describe patients with benefits of its own. The amount of carrier employed in con binge eating disorder or associated symptoms, a history of junction with the compound is Sufficient to provide a practical major depressive episodes, obsessive compulsive behavior, quantity of material for administration per unit dose of the generalized anxiety disorder, or attention deficit hyperactiv compound. ity disorder whose symptoms were poorly managed with 0111. The pharmaceutical dosage forms may contain an psychopharmacologic interventions. In the cases wherebinge amphetamine prodrug, methylphenidate prodrug, or meth eating and depression were present, binge eating behavior ylphenidate analog as the only active agent or may be com significantly lessened following treatment with the amphet bined with one or more additional active agents in the same amine prodrug, lisdeXamfetamine dimesylate; in one of these dosage form. Active agents Suitable for combination with an cases, it was thought that binge eating symptoms were due to amphetamine prodrug, methylphenidate prodrug or meth antidepressant medication and the addition of amphetamine ylphenidate analog in a single dosage form have been listed prodrug lisdexamfetamine dimeSylate decreased binging above in the section titled “Combination Methods.” Particu behavior. Additionally, patients treated with lisdexamfe larly useful combination dosage forms include lisdexamfe tamine dimeSylate, either as a monotherapy or as an adjunct to tamine in combination with at least one of the following in a existing therapies, experienced remission of their depressive single dosage form: orlistat, memantine, naltrexone, acamp symptoms. The examples demonstrate the effectiveness of an rosate, topiramate, Zonisamide, Sibutramine, escitalopram, amphetamine prodrug as a monotherapy or in combination Sertraline, fluoxetine, citalopram, bupropion, Venlafaxine, with one or more other therapeutic agents for treating a range and duloxetine. of psychological symptoms, including binge eating and depression. Tablets and Capsules 0116. These case reports suggest the clinical efficacy of an 0112 Tablets typically comprise conventional pharma amphetamine prodrug, methylphenidate prodrug, or meth ceutically compatible adjuvants as inert diluents, such as ylphenidate analog in the treatment of binge eating disorder calcium carbonate, sodium carbonate, mannitol, lactose and or associated symptoms (in two cases thought to worsen from cellulose; binders such as starch, gelatin and Sucrose; disin antidepressant agents), obesity resulting from binge eating tegrants such as starch, alginic acid and croScarmelose; lubri behavior, and depressive disorders, as either a monotherapy cants such as magnesium Stearate, Stearic acid and talc. or as an adjunct to existing antidepressant pharmacotherapy. Glidants such as silicon dioxide can be used to improve flow In addition these cases also demonstrate that an amphetamine characteristics of the powder mixture. Coloring agents, such prodrug, a methylphenidate prodrug, or methylphenidate as the FD&C dyes, can be added for appearance. Sweeteners analog may offer significant clinical value in treatment of and flavoring agents, such as aspartame, Saccharin, menthol, anxiety spectrum symptoms, include generalized anxiety dis peppermint, and fruit flavors, are useful adjuvants for chew order and obsessive compulsive behavior. able tablets. Capsules (including time release and Sustained release formulations) typically comprise one or more solid Example 1 diluents disclosed above. The selection of carrier components often depends on secondary considerations like taste, cost, Treatment of a Patient with Major Depressive Disor and shelf stability. Such compositions may also be coated by ders and Binge Eating Disorder Using the Amphet conventional methods, typically with pH or time-dependent amine Prodrug Lisdexamfetamine Dimesylate coatings, such that the Subject compound is released in the 0117 Patient 1 is an adult, non-geriatric patient with a gastrointestinal tract in the vicinity of the desired topical history of a major depressive disorder, attention deficit hyper application, or at various times to extend the desired action. activity disorder, and binge eating disorder. Throughout Such dosage forms typically include, but are not limited to, Patient 1's entire adult life, there were reportedly periodic one or more of cellulose acetate phthalate, polyvinylacetate depressive episodes and symptoms. Patient 1 also indicated a phthalate, hydroxypropyl methylcellulose phthalate, ethyl history of binge eating disorder for approximately one year, cellulose, Eudragit coatings, waxes and shellac. characterized by eating unusually large amounts of junk food, 0113 Formulations for oral use may also be presented as often until feeling nauseated, and then feeling very guilty hard gelatin capsules wherein the active ingredient is mixed about the binging behavior. Such symptoms, though intermit with an inert Solid diluent, for example, calcium carbonate, tently present for the past two decades, had escalated to an calcium phosphate or kaolin, or as Soft gelatin capsules average of nearly every other day for about 12 months. During wherein the active ingredient is mixed with water or an oil this time Patient 1 was being treated with PAXIL (paroxetine) medium, for example peanut oil, liquid paraffin or olive oil. and then ZOLOFT (sertraline) daily. Patient 1 participated in 0114. The invention includes amphetamine prodrug cap group therapy to address mood and eating symptoms. How Sule formulations, particularly lisdexamfetamine dimesylate ever, group therapy did not prove helpful for managing the capsule formulations, 2.5 mg to 250 mg, 2.5 mg to 12.5 mg. binging behavior, the number of episodes as well as the 2.5 to 15 mg, 10 to 100 mg per day, 20 to 70 mg per day, or number of days binging continued on average every other US 2010/0166889 A1 Jul. 1, 2010

day. Following group therapy, Patient 1 began to experience a while alone, and until feeling bloated. While the patient worsening depressed mood, poor concentration, and exces struggled with binging behavior for the past two decades, the 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 2's 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 I0120 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 0118 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 I0121 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 2's and Major Depressive Disorders Using Lisdexamfe number of failed treatments of recurrent major depressive tamine Dimesylate disorder. Prior treatments failed due to poor treatment 0119 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 2's ADHD symptoms were notatissue at dependence, major depressive disorder, generalized anxiety 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 intensive psychotherapy and received various forms of Sub Example 3 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 Behavior Using Lisdexamfetamine Dimesylate afternoons and early evenings. While the patient experienced an underlying mild depressive disorder, such “wear off 0.122 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 US 2010/0166889 A1 Jul. 1, 2010

tasks that have been initiated. Symptoms of Generalized nings. Such emotional eating was often triggered by stress Anxiety Disorder included frequent and intense ruminative ful situations or events, accompanied by an urge to eat, and 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 0.125. 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. 0123. 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 Dis enhanced an overall sense of improved well being, effective orders and Binge Eating Behavior with Lisdexamfe ness, and confidence. tamine Dimesylate 0.124. The patient is a non-geriatric adult with a history of Example 5 intermittent major depressive disorder, dysthymic disorder, Treatment of Binge Eating Disorder, Medication and binge eating behavior. The patient also endorsed symp Induced Cognitive Problems, and Fatigue with Lis toms of ADHD, inattentive type, primarily around problems dexamfetamine Dimesylate with organizing tasks, procrastination of work activities, and problems completing projects, though Such inattention 0.126 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), US 2010/0166889 A1 Jul. 1, 2010

LYRICA (pregabalin), and RITALIN (methylphenidate). deal with organizational difficulties, auditory inattention and Selective serotonin reuptake inhibitors exacerbated binge eat forgetfulness, and feeling poorly engaged. However, after ing symptoms and caused problematic weight gain. For treat beginning a new job with more challenging responsibilities, ment of depression with comorbid anxiety, binge-eating, and the patient was unable to compensate for Such deficits and a weight-gain related to binge eating symptoms, the patient was pattern of obsessive ruminations emerged, often involving maintained on a medication regimen that included work. In addition to perseverative and obsessive thinking, the TOPAMAX (topiramate) 175 mg in the morning and 200 mg patient experienced heightened anxiety and mild depressive at night, LAMICTAL (lamotrigine) 200 mg in the morning, symptoms, including fatigue, low mood, and amotivation, CYTOMEL (liothyronine) 25 mcg per day, KLONOPIN especially while at work. After discussing medication options (clonazepam) 0.25 mg at bedtime, and NEURONTIN (gaba and side effect concerns, VYVANSE was initiated to address pentin) 600 mg at bedtime. However, symptoms of depressed underlying ADHD symptoms, which were felt to drive the mood, hopelessness, amotivation, problems with concentra patient's perseverative thinking, anxious ruminations, and tion (possibly worsened with the use of TOPAMAX though low mood. VYVANSE was initiated at 30 mg per day for one prior attempts to decrease the dose exacerbated binge-eating week, and then titrated to 50 mg per day, without adverse symptoms), significant fatigue, and tendency toward emo effect. PAXIL was maintained at 30 mg per day. Over the tional eating and binging significantly increased from base course of the ensuing 9 weeks, the patient reported improve line. Given prior poor response to a number of different ment across ADHD, Generalized Anxiety Disorder, and classes of medication trials, off-label use of VYVANSE was Major Depressive Disorder symptoms. Work function began initiated at 30 mg each morning to target a constellation of to feel easier, with better ability to attend to tasks and more symptoms, including symptoms of major depression, binge efficient performance, improved attention to detail, and feel eating disorder, fatigue, and concentration problems. ing internally less restless. The patient reported a substantial VYVANSE was maintained at 30 mg each morning for weeks reduction in worrying, an approximate 4-5% weight loss over before being discontinued due to adverse effects. These side 2 months of treatment, and improved mood, motivation and effects were excessive appetite Suppression and visual blur energy. ring. However, during the time of treatment, the patient indi I0129. The case report exemplifies the use of the amphet cated a notably reduced urge to binge, fewer absolute binges amine prodrug lisdexamfetamine dimesylate to address mul per week, fewer binge-eating days per week, and improve tiple clinical issues, the most unexpected one being the alle ment in both fatigue and concentration throughout the day. viation in generalized anxiety symptoms, perseverative However, there appeared to be no benefit on the patient's thinking, and obsessive ruminations. The patient's initial pre depressed mood, amotivation, and feelings of hopelessness. senting symptoms in past treatment have been within the class 0127. 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 depression comprising (i) diagnos Anxiety Disorder, Major Depression, and ADHD ing a patient as having depression and (ii) providing an effec with Lisdexamfetamine Dimesylate tive amount of amphetamine prodrug, methylphenidate pro 0128 Patient 6 is a non-geriatric adult with a history of drug, or methylphenidate analog to the patient, wherein the Generalized Anxiety Disorder and Major Depressive Disor amphetamine prodrug, methylphenidate prodrug, or meth der. The patient was maintained on PAXIL (paroxetine) 30 ylphenidate analog is provided as the only active agent or is mg per day following a significant comorbid major depres provided together with one or more additional active agents. sive episode associated with anxiety symptoms, and a history 3. The method of claim 2 wherein the amphetamine pro consistent with Generalized Anxiety Disorder. Treatment drug, methylphenidate prodrug, or methylphenidate analog is with PAXIL had rapidly stabilized both depressive and anxi lisdexamfetamine (L-lysine-D-amphetamine) dimeSylate, ety symptoms and for approximately 2 years the patient was and the lisdexamfetamine dimesylate is administered to the maintained at 30 mg per day with no change in dose. Over this patient. time, the patient had gained approximately 10% of their body 4. The method of claim 2 wherein the amphetamine pro weight. It was periodically addressed that the patient may drug, methylphenidate prodrug, or methylphenidate analog is have experienced previous academic difficulties due to provided as the only active agent. ADHD, inattentive type, though during the course of treat 5. The method of claim 2 wherein the amphetamine pro ment with PAXIL, the patient was generally able to adapt to drug, methylphenidate prodrug, or methylphenidate analog is work pressures and developed compensatory strategies to administered together with one or more other active agent(s). US 2010/0166889 A1 Jul. 1, 2010

6. The method of claim 3 wherein from 2.5 to 200 mg cypromine, isocarboxazid, phenelzine, selegiline, moclobe lisdexamfetamine dimesylate is administered daily. mide, buspirone, tryptophan, pindolol, agomelatine, 7. The method of claim3, wherein 15 to 100 mg lisdexam amibegron, casopitant, delucemine, elzasonan, gepirone, fetamine dimesylate is administered once per day. mecamylamine, milnacipran, miraxion, nemifitide, pexacer font, Saredutant, tofisopam, Vestipitant, VilaZodone, aripipra 8. (canceled) Zole, clozapine, loxapine, olanzapine, paliperidone, quetiap 9. The method of claim 2, wherein the effective amount is ine, risperidone, Sertindole, Ziprasidone, asenapine, an amount effective to decrease depressive symptoms. iloperidonepimavanserin, lithium, Valproic acid, carbam 10. The method of claim 9, wherein the decrease in depres azepine, eslicarbazepine, lamotrigine, levetiracetam, oXcar sive symptoms is a 50% or greater reduction of symptoms baZepine, tiagabine, topiramate, vigabatrin, Zonisamide, rilu identified on a depression symptom rating scale or achieving Zole, Varenicline, L or pharmaceutically active salts or a score less than or equal to 7 on the HRSD7; or less than or prodrugs thereof, or a combination of the foregoing. equal to 5 on the QIDS-SR: or less than or equal to 10 on the 13. (canceled) MADRS. 14. The methods of claim 5, wherein the other active agent 11. The method of claim 5, wherein the one or more other an anti-depressant chosen from mirtazapine, escitalopram, active agent is an antidepressant, a selective serotonin fluoxetine, Sertraline, citalopram, bupropion, Venlafaxine, reuptake inhibitor, a serotonin 5HT receptor partial agonist or dulloxetine, and the pharmaceutically acceptable salts and antagonist, a norepinephrine dopamine reuptake inhibitor, a hydrates of any of the foregoing. serotonin norepinephrine dopamine reuptake inhibitor, a 15-16. (canceled) selective serotonin norepinephrine reuptake inhibitor, a sero 17. A method of using an amphetamine prodrug, meth tonin 5-HT1a partial agonist, a serotonin 5-HT1b agonist, a ylphenidate prodrug, or methylphenidate analog comprising serotonin 5-HT2 antagonist, a serotonin 5-HT6 antagonist, a informing a user that the amphetamine prodrug, meth serotonin-2 antagonist reuptake inhibitor, a serotonin-1 ago ylphenidate prodrug, or methylphenidate analog may be used nist reuptake inhibitor, a mixed serotonin antagonist reuptake to treat depression. inhibitor/partial agonist/dopamine agonist, an alpha-2 18. The method of claim 17 additionally comprising pro antagonist/serotonin 5HT2-3 receptor antagonist, a serotonin viding the user with lisdexamfetamine (L-lysine-D-amphet modulator or stimulator, a mixed serotonin antagonist/mela amine) dimesylate. tonin agonist, a mixed serotonin dopamine antagonist, a tri 19. The method of claim 18, additionally comprising pro cyclic antidepressant, a tetracyclic antidepressant, a bis-aryl viding lisdexamfetamine dimesylate in a container and the Sulphanyl modulator, a beta-3 adrenoreceptor stimulator or informing is by reference to a package insert associated with agonist, a beta-3 adrenoreceptor antagonist, a nicotinic ace the container. tylcholine receptor agonist or antagonist, an enkephalinergic 20. The method of claim 17, wherein the informing is by modulator, an aprepitant, a neurokinin (NK) antagonist, a reference to information material; by reference to a package NK1, 2, or 3 antagonist, a neuropeptide (NP)Yantagonist, a active agent insert, a flyer or an advertisement; by presenta NPY1, 2, or 3, or 5 antagonist, a substance Pantagonist, a tion of information at a seminar, conference, or other educa corticotrophin-releasing hormone (CRH or CRF) antagonist, tional presentation; or by a conversation between a pharma a CRH (or CRF)-1 antagonist, a glucocorticoid receptorago ceutical sales representative and a medical care worker. nist or partial agonist, a glucocorticoid receptor antagonist, a 21-26. (canceled) glucocorticoid receptor type II antagonist, an anti-convul 27. A method of using an amphetamine prodrug, meth sant, a glutamate modulator, an mGluR receptor modulator, ylphenidate prodrug, or methylphenidate analog comprising agonist or antagonist, an mGluR2/3 agonist, an mGluR5 (i) conducting a clinical trial of the efficacy of the amphet antagonist, an estrogen receptoragonist orantagonist, a mela amine prodrug, methylphenidate prodrug, or methylpheni tonin receptor agonist or antagonist, a glycine transporter date analog for treating depression and (ii) informing a pur inhibitor, an alpha-1 receptor agonist, an alpha-1 receptor chaser of the prodrug that the prodrug is efficacious for antagonist, an alpha-2 receptor agonist, an alpha-2 receptor treating depression. antagonist, a vasopressin-1B (V1B) agonist orantagonist, an 28. The method of claim 27 wherein the amphetamine NMDA modulator (i.e., a partial agonist, agonist, or antago prodrug, methylphenidate prodrug, or methylphenidate ana nist), a mood modulating (i.e., stabilizing) agent, a monoam log is lisdexamfetamine (L-lysine-D-amphetamine) dimesy ine oxidase inhibitor, or a combination of the foregoing. late. 12. The method of claim 11, wherein the other active agent 29. The method of claim 27, wherein the clinical trial is clovoxamine, femoxetine, flesinoxan, citalopram, escitalo generates data that is submitted to the FDA. pram, fluoxetine, fluvoxamine, paroxetine, Sertraline, dulox 30. The method of claim 2, wherein the amphetamine etine, desvenlafaxine, mirtazapine, Venlafaxine, atomoxet prodrug, methylphenidate prodrug, or methylphenidate ana ine, reboxetine, thionisoxetine, bupropion, mianserin, log is lisdexamfetamine (L-lysine-D-amphetamine) and 15 to nefazodone, traZodone, doxepin, amitriptyline, amoxapine, 75 mg lisdexamfetamine are administered daily. clomipramine, desipramine, doxepin, imipramine, mapro tiline, nortriptyline, protriptyline, trimipramine, tranyl c c c c c