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US 2004O229941A1 (19) (12) Patent Application Publication (10) Pub. No.: US 2004/0229941A1 HaSSman et al. (43) Pub. Date: Nov. 18, 2004

(54) ANALEPTIC AND Related U.S. Application Data COMBINATIONS (60) Provisional application No. 60/469,989, filed on May (75) Inventors: Howard A. Hassman, Moorestown, NJ 13, 2003. (US); Rodney J. Hughes, Kennett Square, PA (US) Publication Classification Correspondence Address: (51) Int. Cl." ...... A61K 31/343; A61K 31/137 , INC. (52) U.S. Cl...... 514/469; 514/617; 514/649 145 BRANDY WINE PARKWAY WEST CHESTER, PA 19380-4245 (US) (57) ABSTRACT (73) Assignee: Cephalon, Inc., West Chester, PA (21) Appl. No.: 10/844,134 Compositions and methods for the treatment of depressive disorders through the administration of with anti (22) Filed: May 12, 2004 . US 2004/0229941 A1 Nov. 18, 2004

ANALEPTIC AND ANTIDEPRESSANT nocturnal . Pathological Somnolence, whether due to COMBINATIONS or other causes, is disabling and potentially dangerous. Causes of pathological Somnolence, other than BACKGROUND OF THE INVENTION narcolepsy, include chronic Sleep loSS; ; and other sleep disorders. Whether due to narcolepsy or other 0001) 1. Modafinil causes, pathological Somnolence produces episodes of unin 0002 Modafinil, CHNOS, also known as 2-(benzhy tended sleep, reduced attention, and performance errors. drylsulfinyl) acetamide, or 2-(diphenylmethyl) sulfinyl Consequently, it is linked to a variety of transportation and acetamide, is a Synthetic acetamide derivative with wake industrial accidents. A therapeutic agent that reduces or promoting activity, the Structure of which has been described eliminateS pathological Somnolence would have important in French Patent No. 78 05 510 and in U.S. Pat. No. implications not only for individual patients, but also for 4,177.290 (290), and which has been approved by the public health and Safety. United States Food and Administration for use in the 0007. Other uses of modafinil have been presented. U.S. treatment of excessive daytime Sleepiness associated with Pat. No. 5,180,745 discloses the use of modafinil for pro narcolepsy. A method of preparation of a is Viding a neuroprotective effect in humans, and in particular described in the 290 patent and a method of preparation of for the therapy of Parkinson's disease. The levorotatory a levorotatory isomer is described in U.S. Pat. No. 4,927,855 form of modafinil, i.e., (-) benzhydrylsulfinyl-acetamide, (both incorporated herein by reference). The levorotatory may have potential benefit for therapy of depression, hyper isomer is reported to be useful for treatment of , somnia and Alzheimer's disease (U.S. Pat. No. 4,927,855). depression, Alzheimer's disease and to have activity towards European Published Application 547952 discloses the use of the Symptoms of dementia and loSS of memory, especially in modafinil as an anti-ischemic agent. European Published the elderly. Application 594507 discloses the use of modafinil to treat 0003. The primary pharmacological activity of modafinil urinary incontinence. is to promote wakefulness. Modafinil promotes wakefulneSS 0008 U.S. Pat. No. RE37,516 discloses pharmaceutical in rats (Touret et al., 1995; Edgar and Seidel, 1997), cats compositions having a defined particle size, and in particular (Lin et al., 1992), canines (Shelton et al., 1995) and non compositions wherein 95% of the cumulative total of the human primates (Hernant et al., 1991) as well as in models effective amount of modafinil particles in the composition mimicking clinical situations, Such as sleep apnea (English have a diameter less than about 200 microns. bulldog sleep disordered breathing model) (Panckeri et al., 1996) and narcolepsy (narcoleptic canine) (Shelton et al., 0009 2. 1995). 0010 Antidepressants, including selective 0004 Modafinil has also been described as an agent with inhibitors (SSRIs) have become first choice thera activity in the central nervous System, and as a useful agent peutics in the therapy of depression, certain forms of in the treatment of Parkinson's disease (U.S. Pat. No. and Social phobias. In Some instances, SSRIs can be more 5,180,745); in the protection of cerebral tissue from favored because they are effective, well tolerated and have ischemia (U.S. Pat. No. 5,391,576); in the treatment of a favorable Safety profile compared to the classic urinary and fecal incontinence (U.S. Pat. No. 5,401.776); antidepressants. and in the treatment of Sleep apneas and disorders of central 0011. However, there can be problems associated with origin (U.S. Pat. No. 5,612,379). U.S. Pat. No. 5,618,845 any anti-. Current antidepressant therapy can describes modafinil preparations of a defined particle size exhibit a delayed onset and modest proportion in achieving less than about 200 microns. In addition, modafinil may be response or remission. For example, the response at 6 weeks used in the treatment of eating disorders, or to promote to the selective serotonin (SSRI) fluox weight gain or stimulate appetite in humans or animals (U.S. etine is about 50%. Remission rates with SSRIs at 8 weeks Pat. No. 6,455,588, incorporated herein by reference), or in are about 35%. Delayed, incomplete and lack of response of the treatment of attention deficit hyperactivity disorder a major depressive disorder to antidepressant therapy can be (ADHD) (U.S. Pat. No. 6,346,548, incorporated herein by problematic for numerous reasons, including premature reference), or fatigue, especially fatigue associated with treatment discontinuation. Sometimes Symptoms even multiple sclerosis (U.S. Pat. No. 6,488,164, incorporated worsen during the first weeks of therapy. In other cases, herein by reference). non-compliance can be related to Side effects, including 0005) Modafinil has been shown to be effective in treat Sexual dysfunction. ing narcolepsy, sleepiness, excessive sleepiness (e.g., sleepi 0012 Fatigue and excessive sleepiness are among the ness associated with disorders of Sleep and wakefulness), Symptoms of a major depressive disorder, and can be excessive daytime SleepineSS associated with narcolepsy, adverse experiences associated with antidepressant therapy Parkinson's disease, urinary incontinence, multiple Sclerosis and are often residual Symptoms inadequately treated with fatigue, ADHD, Alzheimer's disorder, Sleep apnea, obstruc SSRI antidepressant therapy. tive sleep apnea, depression, and ischemia. 0013 In addition, patients sometimes suffer side effects 0006 Narcolepsy is a chronic disorder characterized by asSociated with antidepressant therapy and withdrawal of intermittent Sleep attacks, persistent, excessive daytime antidepressant therapy. sleepiness and abnormal rapid eye movement (“REM”) Sleep manifestations, Such as sleep-onset REM periods, 0014. Because residual symptoms to antidepressant cataplexy, Sleep paralysis and hypnagogic , or therapy predisposes patients with depression to a greater risk both. Most patients with narcolepsy also have disrupted of relapse and greater probability of recurrence, rapid US 2004/0229941 A1 Nov. 18, 2004

achievement of remission is an important consideration in tyline hydrochloride, , ; ketipramine choosing the most appropriate treatment Strategy. fumarate; hydrochloride, ; mapro tiline; hydrochloride; hydrochloride; 0.015 New therapies that address one or more of these millacemide hydrochloride; hydrochloride; mir problems are needed. tazapine; ; modaline Sulfate, napacitadine hydrochloride; napameZole hydrochloride; SUMMARY OF THE INVENTION hydrochloride; , nitrafudam hydrochloride; 0016. In one embodiment, the present invention includes maleate, hydrochloride; octrip a method of enhancing the activity of an antidepressant in an tyline phosphate, hydrochloride; animal Subject, preferably a human. The method includes hydrochloride; , ; Sulfate; the Step of pre-treating the Subject with an effective amount hydrochloride, pizotyline; hydrochlo of one or more analeptics, including but not limited to ride, hydrochloride; hydrochloride; modafinil and/or co-administering an effective amount of maleate, rolicyprine; hydrochloride; one or more analeptics, including but not limited to modafi hydrochloride; hydrochloride; nil, with an antidepressant. , ; hydrochloride; fumarate; hydrochloride; thiaZeSim hydrochlo DETAILED DESCRIPTION OF THE ride; ; tomoxetine hydrochloride; INVENTION hydrochloride; trebenzomine hydrochloride; ; trimipramine maleate; hydrochloride, Vilox 0.017. 1. Analeptic Agents azine hydrochloride, Zimeldine hydrochloride, . 0.018 Analeptics are that principally act as or are 0022. In certain embodiments, the antidepressant used as a central nervous System . Preferred for use includes citalipram, , fluoxetine hydrochloride, in the practice of the invention are analeptics that operate on paroxetine, paroxetine hydrochloride, and/or the sleep-wake centers of the brain and that lack the phar hydrochloride, with citalipram, paroxetine, fluoxetine and macological effects of . Preferred analeptic fluoxetine hydrochloride preferred, with citalipram most agents have the pharmacological profile of modafinil. Thus, preferred. in a preferred embodiment of the invention, the analeptic used in the practice of the invention is Provigil(R) (modafi 0023. Other drugs which are useful in treating depressive nil). disorders, e.g., , can also be used in the practice of 0019 2. Antidepressants the invention. 0020. Useful antidepressants include but are not limited 0024 3. Variants, Analogs, Salts, Different Forms to tricyclic antidepressants (“TCAS”), Selective Serotonin 0025 Antidepressants not listed above, including but not Reuptake Inhibitors ("SSRIs”), Serotonin and Noradrena limited to Structural analogs of the above compounds, that line Reuptake Inhibitors (“SNRIs'), Reuptake are Safe and effective, are also useful in the practice of the Inhibitors (“DRIs”), Noradrenaline Reuptake Inhibitors invention. (“NRUs”), Dopamine, Serotonin and Noradrenaline 0026 Included within the scope of this invention are the Reuptake Inhibitors (“DSNRIs') and various individual Stereoisomers, including diastereomers Inhibitors ("MAOIs) including reversible inhibitors of and enantiomers (e.g., the L and/or R-isomer of modafinil) monoamine oxidase type A (RIMAS). as well as mixtures thereof. In addition, compounds useful 0021. In certain embodiments, a suitable antidepressant in this invention also include any pharmaceutically accept can include, but is not limited to, one or more of the able Salts, for example: alkali metal Salts, Such as Sodium following antidepressants: hydrochloride; adi and potassium, ammonium Salts, monoalkylammonium nazolam, meSylate, alaprociate, aletamine Salts, dialkylammonium Salts, trialkylammonium Salts, tet hydrochloride; hydrochloride, raalkylammonium Salts, and tromethamine Salts. Hydrates, hydrochloride; , maleate, azaloxan Solvates, and polymorphs of the compounds described above fumarate; , hydrochloride; bipenarnol are included within the scope of this invention. Combina hydrochloride; hydrochloride; butacetin; butrip tions of analeptics and of antidepressants can also be tyline hydrochloride; , , ; employed. The compounds can be Substantially pure or hydrochloride; meSylate, citalipram; mixed with other ingredients. clodazon hydrochloride; clomipramine hydrochloride; coti nine fumarate, cyclindole, hydrochloride; 0027 4. Depressive Disorders cyprolidol hydrochloride, cyproximide; tosylate; 0028. The invention is useful in the treatment of depres hydrochloride; daZadrol maleate, dazepinil Sion, including mild to Severe or acute depression, that may hydrochloride; hydrochloride; dexamisole; be caused by any of a number of factors, including, for deximafen; hydrochloride; dioxadrol hydrochlo example, depression associated with or drug abuse. ride; dothiepin hydrochloride; hydrochloride; The invention is also useful in the treatment of other dulloxetine hydrochloride, maleate, encyprate; disorders for which antidepressants are Sometimes pre hydrochloride; fantridone hydrochloride; feh Scribed. These include, for example, anxiety, StreSS, Social metoZole hydrochloride; , fuma phobia, panic, obsession, compulsive behavior, pain (e.g., rate; hydrochloride; fluoxetine; fluoxetine hydro neuropathic and inflammatory pain) etc. Such disorders, for chloride; hydrochloride; gamfeXine, guanoxyfen which antidepressants have been shown to have clinically Sulfate; imafen hydrochloride, hydrochloride, imi beneficial effects, are herein referred to collectively as pramine hydrochloride; hydrochloride; intrip “depressive disorders.” US 2004/0229941 A1 Nov. 18, 2004

0029) 5. Therapeutically Effective Amounts of Analeptics include a pharmaceutical carrier according to conventional and Antidepressants pharmaceutical compounding techniques, which carrier may 0.030. In one embodiment of the present invention, an take a wide variety of forms depending on the form of amount of analeptic, e.g. modafinil, administered to a patient preparation desired for administration, e.g., oral, by Sup can include 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, pository, or parenteral. The amount of each active compo 200, 300 and/or 400 mg. of modafinil, or combinations nent in the composition can correspond to the amounts thereof. Typically, modafinil can be administered in 50, 75, described above. Pharmaceutically acceptable carriers 100 and 200 mg. amounts. However, when used in combi include, e.g., Stabilizers binders, fillers, disintegrants, lubri nation with one or more antidepressants, as described herein, cants, coatings, Sweeteners, flavors, colors, diluents, etc. the amount of modafinil necessary to alleviate all or a Such a composition, when used for the therapy of a depres portion of the Symptoms associated with antidepressant Sive disorder preferably can include therapeutically effective therapy can be reduced. Accordingly, one embodiment of the amounts of an analeptic and antidepressant. present invention includes 100 mg. or less of modafinil when 0037. In preparing the compositions in oral dosage form, administered with an antidepressant, either as a combined any of the usual pharmaceutical media may be employed. unit dose with the antidepressant or as a separate dose. A Thus, for liquid oral preparations, Such as for example, Single unit dose containing both modafinil and an antide Suspensions, elixirs and Solutions, Suitable carriers and addi preSSant is a preferred composition of the present invention, tives include water, glycols, oils, , flavoring agents, as described below. preservatives, coloring agents and the like; for Solid oral preparations Such as, for example, powders, capsules and 0.031 Typically, one or more antidepressants can be tablets, Suitable carriers and additives include Starches, administered in the amounts known to be effective for each Sugars, diluents, granulating agents, lubricants, binders, dis antidepressant. More Specifically, in the present invention, integrating agents and the like. Because of their ease in an antidepressant can be administered in an amount effective administration, tablets and capsules represent the most to alter the depressive State of an animal Subject, i.e., the advantageous oral dosage unit form, in which case Solid amount of antidepressant that would be administered to the pharmaceutical carriers are obviously employed. If desired, animal Subject if the antidepressant was administered alone. tablets may be Sugar coated or enteric coated by Standard Suitable amounts can include 5, 10, 15, 20, 30, 40, 50, 60, techniques. 70, 80, 90, 100, 200, 300 and/or 400 mg. of a particular antidepressant, and combinations thereof. However, in the 0038 For parenterals, the carrier will usually comprise present invention, when used in combination with one or Sterile water, though other ingredients, for example, for more analeptics Such as modafinil, the overall amount of an purposes Such as aiding Solubility or for preservation, may administered antidepressant can be reduced by 10%, 20%, be included. Injectable Suspensions may also be prepared in 30%, 40%, 50%, 60%, 70% or 80%, while still providing an which case appropriate liquid carriers, Suspending agents antidepressant effect. Accordingly, one embodiment of the and the like may be employed. present invention includes administering less than an 0039. In one embodiment, a pharmaceutical composition amount of antidepressant relative to the amount of antide of the present invention can be administered in a or preSSant administered to an animal Subject if administered capsule form or other suitable unit dose form. A tablet or alone. capsule of the present invention can contain one or more of 0.032 Generally, for daily oral doses of active com the following inactive ingredients: lactose hydrous, prege pounds, the combined total of one or more analeptics and latinized Starch, microcrystalline cellulose, Sodium Starch one or more antidepressants will be from about 0.01 mg/kg glycolate, Stearate, purified water, carnauba per day to about 2000 mg/kg per day. It is expected that IV wax, hydroxypropyl methylcellulose, titanium dioxide, doses in the range of about 1 to 1000 mg/cm per day will polyethylene glycol, Synthetic iron oxide, and polySorbate be effective. 80, etc. 0033. In some embodiments of the present invention, the 0040 Accordingly, a pharmaceutical compositions respective weight ratio of analeptic to antidepressant can be herein Will contain, per dosage unit, e.g., tablet, capsule, from 0.01:1 to 1:1 to 100:1, possibly 1000:1. In some powder injection, teaspoonful, Suppository and the like from embodiments the weight ratio can be 1:1 to 7:1 or 10:1, most about 5 to about 1000 mg, or more, of an analeptic and preferably 1:1 to 5:1. antidepressant. In one embodiment of the invention, each 0034. A dosage form containing an above described Single dosage unit (or unit dose) includes both an amount of amount of an analeptic (e.g., modafinil) and one or more an analeptic and an amount of an antidepressant. In Such antidepressants can provide to a patient improved fatigue embodiment, it is not necessary that each Single dosage unit Symptoms, as well as improve waking functioning, as dem include an effective amount So long as the total amount of drug administered to a patient is an effective amount of each. onstrated by the effects of fatigue, energy, and Therefore, for example, a patient may require 2 or more cognitive function (e.g. psychomotor retardation). Single dosage units to receive effective amounts of both 0035) 6. Preparation of a Composition of the Present agents. Invention 0041 When administered, the formulations of the inven 0036) To prepare a pharmaceutical composition of this tion are applied in pharmaceutically acceptable amounts and invention, an analeptic, including but not limited to modafi in pharmaceutically acceptable compositions. Such prepa nil, and an antidepressant, including but not limited to one rations may routinely contain Salts, buffering agents, pre or more of the antidepressants described above, can be Servatives, compatible carriers, and optionally other thera intimately admixed. The mixture can further optionally peutic ingredients. When used in medicine the Salts should US 2004/0229941 A1 Nov. 18, 2004 be pharmaceutically acceptable, but non-pharmaceutically Systems. Such as polylactic and polyglycolic acid, polyan acceptable Salts may conveniently be used to prepare phar hydrides and polycaprolactone; nonpolymer Systems that are maceutically acceptable Salts thereof and are not excluded lipids including Sterols Such as , cholesterol esters from the Scope of the invention. Such pharmacologically and fatty acids or neutral fats Such as mono-, di and and pharmaceutically acceptable Salts include, but are not triglycerides, hydrogel release Systems, Silastic Systems, limited to, those prepared from the following acids: hydro peptide based Systems, wax coatings, compressed tablets chloric, hydrobromic, Sulfuric, nitric, phosphoric, maleic, using conventional binders and excipients, partially fused acetic, Salicylic, p- Sulfonic, tartaric, citric, methane implants and the like. In addition, a pump-based hardware Sulfonic, formic, malonic, Succinic, naphthalene-2-Sulfonic, delivery System can be used, Some of which are adapted for and Sulfonic. Also, pharmaceutically acceptable implantation. Salts can be prepared as alkaline metal or alkaline earth Salts, 0048. Another embodiment of the present invention pro Such as Sodium, potassium or Salts. vides a kit or device which can facilitate the administration 0.042 Suitable buffering agents include: acetic acid and a of an amount of an analeptic and an antidepressant to treat salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric a depressive disorder. Specifically, a kit according to the acid and a salt (0.5-2.5% W/V); and phosphoric acid and a present invention includes at least one dosage form contain salt (0.8-2% W/V). Suitable preservatives include benzalko ing an analeptic, including but not limited to modafinil, and nium chloride (0.003-0.03% W/V); (0.3-0.9% a separate dosage form containing at least one antidepres W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004 Sant. One Suitable kit of the present invention includes a 0.02% W/V). blister pack having a unit dose of modafinil and a separate unit dose of an antidepressant. Most preferably, the unit dose 0.043 Dosage may be adjusted appropriately to achieve of modafinil includes a 50, 75, 100 or 200 mg. tablet of desired drug levels, locally or Systemically. AS noted above, modafinil and the unit dose of antidepressant includes a 10, generally, daily oral doses of active compounds will be from 20, 30, 40 or 50 mg. tablet of antidepressant. The kit or about 0.01 mg/kg per day to 2000 mg/kg per day. In the device can also include instructions concerning administra event that the response in a Subject is insufficient at Such tion of the analeptic and antidepressant. Preferably, the doses, even higher doses (or effective higher doses by a instructions provide administration guidance according to different, more localized delivery route) may be employed to one or more of the administration schemes set forth below. the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day 0049. The analeptic and/or antidepressant can be in any is contemplated to achieve appropriate Systemic levels of Suitable dosage form, including but not limited to Solid compounds. dosage forms including tablets, capsules, pills, troches, cachets, and the like, and/or liquid dosage forms Such as an 0044) A variety of administration routes are available. oral elixir or an IV fluid. The dosage form of the analeptic The particular mode Selected will depend of course, upon the can be the same type or a different type than the antidepres particular drug selected, the Severity of the disease State(s) Sant. being treated and the dosage required for therapeutic effi cacy. The methods of this invention, generally speaking, 0050. In yet another embodiment, the present invention may be practiced using any mode of administration that is includes a transdermal drug delivery system (“TDDS”). A medically acceptable, meaning any mode that produces TDDS suitable for use with the invention in patch form effective levels of the active compounds without causing typically contains at least: (1) a backing layer and (2) a clinically unacceptable adverse effects. Such modes of carrier formulated with an effective amount of an antide administration include oral, rectal, Sublingual, topical, nasal, preSSant and optionally modafinil. transdermal or parenteral routes. The term "parenteral' 0051 Preferred patches include (1) the matrix type patch; includes Subcutaneous, intravenous, intramuscular, or infu (2) the reservoir type patch; (3) the multi-laminate drug-in SO. adhesive type patch; and (4) the monolithic drug-in-adhesive 004.5 The compositions may conveniently be presented type patch. These patches are generally available commer in unit dosage form and may be prepared by any of the cially. methods well known in the art of pharmacy. In general, the 0052 For practice of the invention, the matrix type and compositions are prepared by uniformly and intimately the drug-in-adhesive type patches are especially preferred. bringing the compounds into association with a liquid car The more preferred drug-in-adhesive patch is the monolithic rier, a finely divided Solid carrier, or both, and then, if type. necessary, shaping the product. 0053 Transdermal drug delivery systems other than stan 0.046 Compositions suitable for oral administration may dard patches can also be used. These include, for example, be presented as discrete units Such as capsules, cachets, oSmotic pump systems, ultraSonic Systems, ointments, tablets, or lozenges, each containing a predetermined pastes, gels, medicated powders, creams, lotions, aerosols, amount of the active compound. Other compositions include Sprays, foams, medicated adhesives and the like. Suspensions in aqueous liquors or non-aqueous liquids Such as a Syrup, an elixir, or an emulsion. 0054 7. Method of Treatment/Therapy 0047. Other delivery systems can include time-release, 0055 A. Administration Schemes and Timing of Treat delayed release or Sustained release delivery Systems. Such ment of an Analeptic and Antidepressant Systems can avoid repeated administrations of the active 0056 An analeptic and an antidepressant can be com compounds of the invention, increasing convenience to the bined together into a single unit dose, but can also be Subject and the physician. They include polymer based administered Separately as two or more distinct doses. US 2004/0229941 A1 Nov. 18, 2004

0057 Thus, in some embodiments of the invention, a antidepressant therapy has ended. Preferably, this is accom treatment of a disorder related to depression can be through plished by administering an amount of the analeptic to the the use of Separate dosage forms-one or more analeptic patient and the administration of which can continue for 1, doses and one or more antidepressant doses. Accordingly, a 2, 5, 10, 20, or 30 days, or more, after antidepressant therapy dose of an analeptic can be administered at a different time cessation. relative to the antidepressant dose or simultaneously (i.e., analeptic dose administration within less than 1 hour before 0062. In embodiments where the analeptic and antide or after administration of the antidepressant). However, if preSSant are in Separate dosage forms, the administration of Simultaneous administration is desired, the administration of the analeptic can preferably occur within moments, or in leSS the analeptic and antidepressant can also be through the use than 1 hour, or less than 5 hours, or less than 24 hours or leSS of a Single unit dose including both an analeptic and anti than 48 hours, or less than 72 hours before or after admin depressant. istration of the antidepressant, unless otherwise indicated by a particular method of treatment below. 0.058. In patients that are beginning antidepressant 0063 B. Enhancing Antidepressant Activity therapy, i.e. patients that are Substantially free of antidepres Sants or patients that have been free of antidepressant 0064. In one embodiment, the present invention includes therapy for about 1 week, 2 weeks, more preferably about 4 a method of enhancing the activity of an antidepressant in an or more weeks, the dosage form containing the analeptic can animal Subject, preferably a human. The method includes be administered before and/or at about the Same time as an the Step of pre-treating the Subject with an effective amount initial administration of the antidepressant. In Such an of one or more analeptics, including but not limited to embodiment, one or more administrations of an analeptic modafinil. The amount of analeptic and duration of pretreat can be within 72 hours, preferably within 48 hours, more ment can vary from Subject to Subject, but typically con preferably within 24 hours, most preferably within 1 hour or forms to the amounts described above and one or more of the moments before an initial administration/dosing of an anti timing Schemes Set forth above. depressant. After the initial administration of the analeptic 0065 However, in one particular embodiment, the and antidepressant, Subsequent dosings of the analeptic and amount of analeptic includes an effective amount, typically antidepressant can continue at a typical rate, e.g., typically from about 100 mg to about 200 mg of modafinil adminis one or two 50, 75, 100 to 200 mg. doses of modafinil per day tered once or twice daily for a period of less than 2 days, and 10, 20, 30, 40, 50 mg. of antidepressant per day. Further, preferably less than 10 days, prior to the initiation of after the initial administration of the antidepressant, the antidepressant therapy. The administration of the analeptic dosings of the analeptic and antidepressant can be in Sepa can also optionally continue during antidepressant therapy rate dosage forms or in a Single unit dose. However, if a dose and also continue for a period of time after the cessation of of an analeptic is to be administered before a Subsequent antidepressant therapy, as described above. dose of an antidepressant, Separate dosage forms for each are preferred. 0066. The analeptic can be administered orally, nasally, rectally, intravenously, epidurally, intraperitoncally, Subcu 0059 Additionally, in patients that are substantially free taneously, intramuscularly or intrathecally. of antidepressants, the initial administration of the analeptic can coincide with or be nearly simultaneous with the initial 0067. Definitions administration of an antidepressant. This can be accom 0068 “Particle,” as used herein, refers to an aggregated plished through the use of Separate dosage forms of an physical unit of the acetamide compound, i.e., a piece or a analeptic and antidepressant which can then be administered grain of acetamide. together simultaneously (i.e., within 1 hour or less, before or after the antidepressant) or through the use of a single unit 0069. As used herein, “about” means plus or minus ten dose including both an analeptic and an antidepressant, as percent of the indicated value, such that “about 20 mg” noted above. indicates 18 to 22 mg. 0060) Further, an analeptic, including but not limited to 0070 AS used herein, “consisting essentially of refers to modafinil, can also be administered to a patient that has excluding other active ingredients but including excipients already received at least an initial dose of an antidepressant. and additional amounts of the active ingredient to account In one embodiment, the initial administration of an analeptic for degradation or otherwise. can be within 72 hours, preferably within 48 hours, more 0071 An “effective amount,” as used herein, is an preferably within 24 hours, most preferably within 1 hour or amount of modafinil and/or antidepressant that is effective within moments after the initial administration of an anti for treating a depressive State, i.e., an amount of modafinil depressant. In this timing Scheme, modafinil is administered and/or antidepressant that is able to reduce, alleviate or at about the same time as an antidepressant, but Subsequent eliminate certain Symptoms associated with depression and/ to at least one administration of an antidepressant. After the or antidepression therapy. initial dosing of an analeptic, the dosing of the analeptic and antidepressant can continue in a typical manner. In one 0072 A “pharmaceutical composition,” as used herein, particularly preferred embodiment, initial administration of means a medicament for use in treating a mammal that an analeptic and Subsequent administrations of an analeptic comprises modafinil prepared in a manner that is appropriate can be accomplished through the use of a Single unit dose for administration to a mammal. A pharmaceutical compo including both an analeptic and an antidepressant. Sition according to the invention may also, but does not of necessity, include a non-toxic pharmaceutically acceptable 0061. In a further embodiment, initial administration of carrier. A pharmaceutical composition can also include bulk an analeptic to a patient can occur and/or continue after active modafinil for use in preparing dosage forms. A US 2004/0229941 A1 Nov. 18, 2004

pharmaceutical composition can also include modafinil in 3. The method of claim 2 wherein the antidepressant is combination with another active, preferably and antidepres Selected from the group consisting of citalipram, fluoxetine, sant, more preferably an SSRI. fluoxetine hydrochloride, paroxetine, paroxetine hydrochlo 0073 While this invention has been disclosed with ref ride, and clomipramine hydrochloride. erence to Specific embodiments, it is apparent that other 4. The method of claim 3 wherein the antidepressant is embodiments and variations of this invention may be fluoxetine or paroxetine. devised by others skilled in the art without departing from 5. The method of claim 1 wherein the modafinil is the true Spirit and Scope of the invention. The appended administered before or Simultaneously with an administra claims are intended to be construed to include all Such tion of an antidepressant to the Subject. embodiments and equivalent variations. Further, the con 6. The method of claim 1 wherein the modafinil is tents of all references cited herein are hereby incorporated administered after the cessation of administration of the by reference. antidepressant to the Subject. What is claimed is: 1. A method for enhancing the activity of an antidepres 7. The method of claim 1 wherein an amount of antide Sant in an animal Subject comprising administering an pressant to be administered includes 5, 10, 15, 20, 30, 40, 50, effective amount of modafinil to the subject. 60, 70, 80, 90, 100, 200, 300 or 400 mg of antidepressant. 2. The method of claim 1 wherein the antidepressant is 8. The method of claim 1 wherein the amount of modafinil Selected from the group consisting of , Selective includes 5, 10, 15, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, Serotonin reuptake inhibitors, Serotonin and noradrenaline 200, 300 or 400 mg of modafinil. reuptake inhibitors, monoamine oxidase inhibitors, and monoamine oxidase type A.