WO2008118785A2 - Methods for treating depression using immediate-impact treatments and d-cycloserine - Google Patents

Abstract

Methods are provided for treating depression in humans. The methods comprise administering D-cycloserine to a subject and administering an immediate-impact depression treatment. Exemplary immediate-impact treatments for depression include administration of ketamine, as well as non-pharmacologic treatments such as electroconvulsive shock therapy.

Description

METHODS FOR TREATING DEPRESSION USING IMMEDIATE-IMPACT TREATMENTS AND D-CYCLOSERINE

RELATED APPLICATIONS

[0001] This application claims priority to U.S.S.N 60/896,556, filed March 23, 2007, and hereby incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] This invention relates to methods and compositions for the treatment of depression in humans that include administering an immediate-impact treatment and D-cycloserine (DCS).

BACKGROUND

[0003] Immediate-impact treatments for depression include acute administration of pharmacological agents such as ketamine, as well as non-pharmacologic treatments such as electroconvulsive shock therapy (ECT). These immediate-impact treatments are particularly useful for subjects with severe depression who need more immediate relief than is typically provided by standard pharmacological remedies, e.g. by administering selective serotonin reuptake inhibitors (SSRIs). Such pharmacological agents commonly take up to three weeks before positive effects are observed. ECT is also frequently performed on subjects for whom pharmacological agents has not been effective. [0004] While immediate-impact treatments can be quite effective in improving depression, maintaining these beneficial effects can be problematic.

[0005] N-methyl-D-aspartate (NMDA) receptor antagonists, administered systemically or infused directly into the amygdala, have been shown to block extinction, e.g. block an action whereby a previously fear conditioned patient is exposed repeatedly to a fear-eliciting cue in the absence of any aversive event, and the fear conditioned response declines. DCS, on the other hand, has been shown to facilitate consolidation of a new learning that competes with a previously conditioned response. For example, DCS has been used together with psychotherapies that promote extinction, such as cognitive behavioral therapy.

[0006] Accordingly, there is a need for improved methods of treating depression in humans that maintain and/or improve the beneficial effects of immediate impact treatments. SUMMARY

[0007] Methods are provided for treating depression in humans. Methods for treating depression in a subject disclosed herein include those methods comprising administering to a subject in need thereof: a) a composition comprising a therapeutically effective amount of D- cycloserine; and b) an immediate-impact depression treatment, wherein said immediate-impact depression treatment is administered within six hours of administering said D-cycloserine. In some embodiments, a sub-antimicrobial dose of D-cycloserine is administered and/or can be administered on an acute basis. For example, between about 10 mg and about 100 mg D- cycloserine can be administered. The composition comprising a D-cycloserine may administered, for example, within about four hours of administering said immediate-impact depression treatment or within about two hours of administering said immediate-impact depression treatment.

[0008] The disclosed immediate-impact depression treatment may comprise a composition comprising a therapeutically effective amount of a second pharmacologic agent, for example, ketamine or a pharmaceutically acceptable salt thereof, or the immediate-impact depression treatment may comprise electroconvulsive shock therapy.

[0009] The methods may comprise D-cycloserine administered before, after, or substantially simultaneous with administration of said immediate-impact depression treatment. The compositions may each be administered intravenously. [0010] In some embodiments, a subject treated by the disclosed methods has more improvement in depression symptoms as measured by a clinical assessment method as compared to improvement in depression symptoms by administration of an immediate depression treatment alone. [0011] Methods are also provided for improving the efficacy of an immediate-impact treatment for depression, comprising administering to a subject in need thereof a composition comprising D-cycloserine within six hours of administering the immediate-impact treatment to said subject. A composition comprising D-cycloserine may be administered between about 1 hour and about 8 hours after, between about 1 hour and about 6 hours, or between 1 hour and about 4 hours after, for example, administration of ketamine or a pharmaceutically acceptable salt thereof. Alternatively, a composition comprising D-cycloserine can be administered between about 5 minutes and about 1 hour, or between about 5 minutes and 2 hours, after administration of electroconvulsive shock therapy. [0012] In some embodiments, improved efficacy of an immediate impact treatment is measured by a clinical assessment test, for example, the disclosed methods may improve the efficacy of an immediate impact treatment in a subject over a longer period of time as compared to the efficacy of administering to a subject an immediate impact treatment alone, as measured by a clinical assessment test.

[0013] Also contemplated herein is an anti-depressive composition comprising ketamine or pharmaceutically acceptable salts thereof, and between about 10 mg and 100 mg D-cycloserine. A kit for use in treating a patient with depression is also provided, that comprises: a composition suitable for administration to a patient comprising D-cycloserine; a composition suitable for administration to a patient comprising ketamine or the pharmaceutically acceptable salts thereof; and instructions for use.

DETAILED DESCRIPTION

[0014] The present invention is directed to methods and compositions for treating depression. The disclosed methods comprise administering to a subject in need thereof an effective amount of an agonist or partial agonist of N-methyl-D-aspartate and an immediate- impact depression treatment. In one aspect, a disclosed method for treating depression in subject includes administering to a subject in need thereof a) an effective amount of D- cycloserine; and b) an immediate-impact depression treatment, wherein said immediate-impact depression treatment is administered before, during or after administering D-cycloserine, e.g. administered within six hours of administering said D-cycloserine.

[0015] Depression refers to the clinical condition known as major depressive disorder, and is characterized by a state of intense sadness, melancholia, or despair that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living. This disclosure relates to treating a patient for depression, wherein "treat" or "treating" refers to an earnest attempt to alleviate depression. In a preferred embodiment, such treatment alleviates depression in a subject or patient. Depression is alleviated if either (or both) the severity or frequency of a symptom of the depression is reduced. However, a subject can be treated for depression in accordance with the methods of the invention irrespective of whether the treatment actually was successful in alleviating the depression. [0016] An immediate-impact treatment for depression is a non-chronic treatment for depression, other than psychotherapy, that can significantly alleviate depression in a subject within about 24 hours of administration of the treatment. In other words, an immediate-impact treatment is not typically a chronic treatment for depression; rather, an immediate-impact treatment is undertaken with the intent of achieving a rapid alleviation of depression.

Exemplary immediate-impact treatments for depression include administration of ketamine and ECT.

[0017] Unlike an immediate impact treatment for depression, chronic treatment of depression is actively and intentionally performed either (i) with reasonable frequency for a period exceeding thirty days, or (ii) on four or more days within a week. For example, traditional vagus nerve stimulation is a chronic treatment, since the stimulation is provided on a daily basis. Traditional pharmacological therapy for depression is a chronic treatment, requiring daily dosages of pharmacological agents such as selective serotonin reuptake inhibitors. [0018] D-cycloserine, or DCS, refers to the chemical D-cycloserine (CA Index Name: 3- Isoxazolidinone, 4-amino-, (4R)- (9CI); CAS Registry No. 68-41-7), or pharmaceutically acceptable salts thereof. DCS is an FDA (United States Food and Drug Administration)- approved drug for treatment of tuberculosis, and is sold by Eli Lilly and Company under the trade name Seromycin®. DCS is a structural analog of D-alanine, and is a broad-spectrum antibiotic produced by some strains of Streptomyces orchidaceus and S. garphalus. DCS has antibiotic activity in vitro against growth phase Gram-negative bacteria such as Escherichia coli, some strains of Staphylococcus aureus, and Chlamydia species, among others. The minimum inhibitory concentrations (MIC) in vitro for typical Mycobacterium tuberculosis strains range from about 6-25 μg/mL. [0019] For the treatment of tuberculosis, DCS is generally dosed at 500-1000 mg/day divided twice daily (PDR 1997) with chronic treatment. At a dose of 500 mg/day, serum concentrations of 25-30 μg/ml are generally maintained. The peak serum concentrations occur within 3-8 hours after dosing, and it is primarily renally excreted with a half-life of 10 hours. [0020] At these typical doses for the treatment of tuberculosis, DCS can give rise to significant neurological side effects in treated subjects. Typical side effects on chronic dosing schedules (who were generally chronically ill with tuberculosis) include drowsiness, depression, headache, confusion, tremor, vertigo, and memory difficulties, paresthesias, and seizure.

[0021] As contemplated herein, a therapeutically effective amount of DCS is lower than the amounts typically used for the treatment of tuberculosis. A "therapeutically effective amount" or "therapeutically effective dose" of the pharmacologic agent is an amount of the pharmacologic agent that typically results in e.g. a greater therapeutic benefit, or a therapeutic benefit for a longer time, relative to that observed in the absence of administering the pharmacologic agent.

[0022] In some embodiments, a therapeutically effective amount of DCS used in the disclosed methods of treating depression relates to a sub-antimicrobial dose of DCS. A sub- antimicrobial dose refers to a dose of DCS that is less than or equal to 2 mg DCS per kg body weight of the subject (i.e., less than or equal to 2 mg/kg), and greater than about 0.4 mg/kg (this lower limit is needed to maintain efficacy for facilitation of extinction). When administered to a subject, sub-antimicrobial doses of DCS achieve peak serum concentrations in the subject of less than or equal to about 5 μg/mL, although there is substantial variability between subjects. At these low concentrations of DCS, the drug no longer kills most microorganisms, including those that are ordinarily susceptible to higher DCS concentrations typically reached in the body when DCS is used to treat tuberculosis (i.e., 500 mg or 1000 mg per day). Obviously, the serum concentration levels of DCS in subjects administered DCS are a function of numerous factors, including body weight, metabolism, and the amount of drug ingested. Furthermore, all microorganisms do not have the same susceptibility to DCS. Accordingly, while it is possible that a sub-antimicrobial dose of DCS can still kill a small subset of microorganisms, sub- antimicrobial doses of DCS generally will not have a significant antimicrobial effect in the body. When administered to adult human subjects, a sub-antimicrobial dose of DCS generally comprises a drug formulation (e.g., pill, capsule, tablet) of DCS containing DCS in an amount equal to or less than 100 mg, preferably less than 80 mg DCS (e.g. about 5 mg to about 100 mg, or about 10 mg to about 100 mg, or even about 10 mg to about 80 mg) to provide a greater margin between the concentration of DCS and the minimum inhibitory concentration (MIC) of DCS against microorganisms active in a subject's body. Children being administered DCS for treatment of tuberculosis are normally dosed at a level between about 10-20 mg/kg. A sub- antimicrobial dose of DCS, when administered to a child subject according to the methods of the present invention, comprises less than or equal to 2 mg/kg, and generally achieves peak serum concentrations of DCS in the child subject of less than or equal to 5 μg/mL. [0023] Because the dosages of DCS contemplated herein are lower than those used to treat tuberculosis, the side effects of DCS will be greatly reduced by infrequent dosing at concentrations five to twenty-fold lower than those routinely used for TB treatment. [0024] The disclosed methods include administering DCS and an immediate-impact treatment for the treatment of depression. The DCS may be administered within about six hours of the commencement or termination of an immediate-impact treatment for depression, e.g. within about 1 to about 6 hours, within about 1 to 4 hours, or within about 1 to 2 hours. DCS may be administered before or after administering an immediate-impact treatment. Alternatively, the DCS may be administered substantially at the same time as an immediate impact treatment. [0025] In some embodiments, DCS is administered on an acute basis. Acute administration of a pharmacological agent to a subject generally refers to a single exposure of the subject or patient to a therapeutically effective amount of the pharmacological agent within an extended time period, i.e. a time period of two, three, or four days or longer. For example, a once, twice or thrice-weekly administration of DCS constitutes acute administration. Administering a single dose of DCS, wherein the dose is formulated to have both immediate release and delayed release characteristics, constitutes acute dosing provided that the peak blood level of DCS in the subject is achieved within 12 hours of the time the dose is administered. [0026] The timing of administration and the therapeutically effective dose of DCS in a given subject will depend on the severity of symptoms, in addition to the age, sex, and size of the subject being treated, among other variables. Preferably the serum concentration of DCS in a subject will be at least 1 μg/mL in order to facilitate consolidation of the immediate-impact treatment for depression.

[0027] In general, the timing of administration of DCS according to the present invention will be within about six hours, more preferably within about three hours, prior to an immediate- impact treatment for depression, or within about six hours, more preferably within about three hours, following an immediate-impact treatment for depression. For example, if a therapeutically effective dose of DCS is administered to a subject two hours prior to a non- pharmacological immediate-impact treatment for depression, then DCS will be present at therapeutically effective levels both before and after the immediate-impact treatment for depression.

[0028] It is contemplated that other agents may be also administered before, during, or after the administration of an immediate impact depression treatment and/or DCS. For example, a B vitamin, such as one or more of the B-complex vitamins, can be administered to a subject in addition to DCS, as part of the contemplated methods. A B-complex vitamin includes thiamine (Bl), riboflavin (B2), niacin (B3), pyridoxine (B6), folic acid (B9), cyanocobalamin (B 12), pantothenic acid and biotin. For example, pyridoxine can be additionally administered at up to ten times the dosage of DCS. In an embodiment, the DCS for administeriation as contemplated herein is provided in a composition that includes a B -complex vitamin, e.g. pyridoxine, for a example, as a tablet or other composition that includes for example 50 mg DCS and 50 mg pyridoxine. DCS has been reported to reduce the levels of certain important chemicals in the blood of subjects, including calcium, folic acid, magnesium, vitamin K, and vitamin B6 and vitamin B 12. Co-administration of DCS with supplements of any of these ingredients is contemplated by the methods and compositions of this invention.

[0029] A subject undergoing treatment with the methods of the invention can experience significant improvements in depression. Relative to subjects treated only with immediate- impact treatments for depression, subjects treated according to the methods of the invention (i.e., subjects administered DCS in conjunction with the immediate-impact treatment for depression) will experience greater improvements, or more long-lasting improvements, as measured by any clinically recognized assessment method for depression (e.g., the 21 -item Hamilton Depression Rating Scale). It should be noted that not every subject will benefit from the methods of the invention, just as other pharmaceutical agents do not typically benefit every patient.

[0030] There are a number of chronic, non-pharmacological treatments for depression, including chronic deep brain therapy, vagus nerve stimulation, light therapy, and repetitive transcranial magnetic stimulation, many of which are performed on a daily basis. DCS can be administered on a chronic basis in conjunction with these treatments, but it is likely that a tolerance to DCS would quickly be established, and the benefits of administering DCS in conjuction with these chronic treatments may be minimal. Alternatively, it is possible to administer DCS on an acute basis, in conjunction with a small subset of a series of these or other chronic treatments (e.g., DCS could administered on a once-weekly basis in conjunction with a daily treatment using vagus nerve stimulation), but with minimal benefit.

Electroconvulsive Shock Therapy [0031] The methods of the invention contemplate treatment of depression in a subject by administering DCS and ECT. Preferably, DCS will be administered subsequent to administration of ECT.

[0032] ECT is a medical procedure wherein an electrical current is passed through the brain of a subject to induce a seizure. Typically, the procedure is performed on an in-patient basis up to three times per week, although maintenance ECT may be performed less frequently on an outpatient basis. The subject is anesthetized, and then the muscles are temporarily paralyzed, often via administration of succinylcholine. In bilateral ECT, electrodes are placed above each temple. In unilateral ECT, the electrodes are placed above the temple of one side of the brain and in the middle of the forehead. An electric current is then applied, triggering a seizure, preferably of duration between about 30 seconds and about 60 seconds. When ECT is performed properly, the subject's body does not convulse and the subject does not experience pain.

[0033] It is not fully understood how ECT works to improve depression, but the biochemistry of the brain is substantially altered during and after seizure activity. By administering DCS in conjunction with ECT, the beneficial changes derived from the ECT may be consolidated, ideally reducing the number of ECT treatments and extending the duration of their efficacy. Typically, ECT is administered up to three times a week for a period of two to four weeks. According to the methods of the invention, DCS can be administered in conjunction with all of these ECT sessions, or, preferably, in conjunction with one or two ECT sessions per week.

[0034] Since an intravenous (IV) catheter is typically inserted into a subject undergoing ECT, it is preferable to administer DCS intravenously through the catheter, rather than via oral dosing or other forms of dosing. In preferred embodiments, DCS is administered subsequent to the termination of the induced seizure, preferably within thirty minutes. [0035] A subject with depression may undergo ECT while being monitored by an electroencephalogram (EEG). In an exemplary embodiment, 50 mg DCS is administered intravenously after the EEG levels off following the seizure and before the subject has awakened from anesthesia. [0036] In another embodiment, a subject with depression may undergo ECT three times per week for three weeks. During each ECT session, for example, 75 mg DCS may be administered intravenously to the subject within ten minutes of the conclusion of the induced seizure, as monitored by EEG. Alternatively, during one ECT session each week, 100 mg DCS can be administered intravenously to the subject within ten minutes of the conclusion of the induced seizure, as monitored by EEG.

Administration of Ketamine

[0037] Ketamine refers to the chemical ketamine (IUPAC name: 2-(2-chlorophenyl)-2- methylamino-cyclohexan-1-one, CAS Registry No. 6740-88-1), or pharmaceutically acceptable salts thereof, most typically the hydrochloride salt. Ketamine is a general dissociative anaesthetic for human and veterinary use.

[0038] The methods of the invention contemplate treatment of depression in a subject by administering DCS and administering ketamine to a subject in need thereof. Preferably, DCS is administered subsequently to administration of ketamine, preferably within about six hours after administration of ketamine, more preferably between about one hour and four hours after administration of ketamine. Also contemplated herein is a composition comprising ketamine and about 10-100 mg of DCS.

[0039] Typically, an intravenous (IV) catheter is inserted into a subject undergoing ketamine treatment for depression. It is preferable, according to the methods of the invention, preferable to administer DCS intravenously through the inserted catheter, rather than via oral dosing or other forms of dosing.

[0040] Following intravenous administration, the ketamine concentration has an initial slope (known as the alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes. This first phase corresponds clinically to the anesthetic effect of the drug. The anesthetic action is terminated by a combination of redistribution from the central nervous system to slower equilibrating peripheral tissues and by metabolic transformation. The later half-life of ketamine (beta phase) is about 2.5 hours. Subsequent administration of DCS, a partial NMDA receptor agonist, changes the dynamics at the NMDA receptor, and the transformation of the effects on the receptor to a net agonist is important in order to consolidate the benefits of the ketamine treatment.

[0041] In an exemplary embodiment, a subject with depression is administered an intravenous infusion of ketamine hydrochloride with a dosing of, for example, 0.5 mg/kg. Two hours later, 50 mg DCS is administered intravenously to the subject. Alternatively, four hours later, 80 mg DCS is administered intravenously to the subject.

Formulation of Pharmaceutical Compositions

[0042] Pharmaceutical compositions contemplated by the methods of the invention may be formulated and administered to a subject for treatment of depression as described below.

[0043] The invention encompasses the preparation and use of pharmaceutical compositions comprising DCS as an active ingredient useful for treatment of depression. Such pharmaceutical compositions may consist of DCS alone, in any form suitable for administration to a subject, or the pharmaceutical composition may comprise DCS and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient(s) may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art. [0044] As used herein, the term "pharmaceutically acceptable carrier" means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject. [0045] As used herein, the term "physiologically acceptable" ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.

[0046] Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention may vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0047] Formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), or as drop infusion preparations. [0048] Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents [0049] The terms "parenteral administration" and "administered parenterally" are art- recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. [0050] Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, intravenous, parenteral, topical, pulmonary, intranasal, buccal, sub-lingual, ophthalmic, intrathecal or another route of administration. For example, a first composition comprising ketamine and a second composition comprising DCS may be packaged in kit form to facilitate use in the disclosed methods. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.

[0051] A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion. As used herein, an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.

[0052] A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface active agents include, but are not limited to, sodium lauryl sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

[0053] Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

[0054] Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. [0055] Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use. [0056] Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, and hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, as well as condensation products of an alkylene oxide with either: a fatty acid, a long chain aliphatic alcohol, a partial ester derived from a fatty acid and a hexitol, or a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0057] Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0058] Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

[0059] A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

[0060] The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

INCORPORATION BY REFERENCE

[0061] All publications, patents, and patent applications cited herein are hereby expressly incorporated by reference in their entirety and for all purposes to the same extent as if each was so individually denoted. EQUIVALENTS

[0062] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. Contemplated equivalents of the methods of treating depression disclosed here include administering compounds and immediate impact treatments which otherwise correspond thereto, and which have the same general properties thereof, wherein one or more simple variations of substituents or components are made which do not adversely affect the characteristics of the methods and compositions of interest. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0063] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0064] Any ranges cited herein are inclusive, e.g., "between about 50 mg and 100 mg" includes compositions of 50 mg and 100 mg. [0065] What is claimed is:

Claims

L A method for treating depression in a subject, comprising administering to a subject in need thereof: a) a composition comprising a therapeutically effective amount of D- cycloserine; and b) an immediate-impact depression treatment, wherein said immediate-impact depression treatment is administered within six hours of administering said D-cycloserine.

2. The method of claim 1, wherein a sub-antimicrobial dose of D-cycloserine is administered.

3. The method of claim 1 or 2, wherein said composition comprising a D- cycloserine is administered within about four hours of administering said immediate-impact depression treatment.

4. The method of any one of claims 1-3, wherein said composition comprising a D- cycloserine is administered within about two hours of administering said immediate-impact depression treatment.

5. The method of any one of claims 1-4, wherein said composition comprising a D- cycloserine is administered on an acute basis.

6. The method of any one of claims 1-5, wherein between about 10 mg and 100 mg D-cycloserine is administered.

7. The method of any one of claims 1-6, wherein said immediate-impact depression treatment comprises a second composition comprising a therapeutically effective amount of a second pharmacologic agent.

8. The method of any one of claims 1-6, wherein said immediate-impact depression treatment comprises electroconvulsive shock therapy.

9. The method of any one of claims 1-8, wherein said composition comprising a D- cycloserine is administered before administration of said immediate-impact depression treatment.

10. The method of any one of claims 1-8, wherein said composition comprising a D- cycloserine is administered after administration of said immediate-impact depression treatment.

11. The method of any one of claims 1-8, wherein said composition comprising a D- cycloserine and said immediate-impact depression treatment are administered substantially simultaneously.

12. The method of claim 7, wherein said second pharmacologic agent is ketamine, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein said second composition is administered intravenously.

14. The method of any one of claims 1-13, wherein said composition comprising D- cycloserine is administered intravenously.

15. The method of any one of claims 1-14, wherein said subject has more improvement in depression symptoms as measured by a clinical assessment method as compared to improvement in depression symptoms by administration of an immediate depression treatment alone.

16. A method for improving the efficacy of an immediate-impact treatment for depression, comprising administering to a subject in need thereof a composition comprising D- cycloserine within six hours of administering the immediate-impact treatment to said subject.

17. The method of claim 16, wherein said composition comprises between about 10 mg and about 100 mg D-cycloserine.

18. The method of claim 16, wherein said immediate-impact treatment comprises administration of ketamine or a pharmaceutically acceptable salt thereof, to said subject.

19. The method of claim 16, wherein said immediate-impact treatment comprises administration of electroconvulsive shock therapy to said subject.

20. The method of claim 18, wherein said composition is administered between about 1 hour and about 6 hours after administration of ketamine or a pharmaceutically acceptable salt thereof.

21. The method of claim 18, wherein said composition is administered between about 1 hour and about 4 hours after administration of said ketamine or a pharmaceutically acceptable salt thereof.

22. The method of claim 19, wherein said composition is administered between about 5 minutes and about 1 hour after administration of said electroconvulsive shock therapy.

23. The method of any one of claims 16-22, wherein improved efficacy of an immediate impact treatment is measured by a clinical assessment test.

24. The method of any one of claims 16-23, wherein the efficacy of the immediate impact treatment is improved in a subject over a longer period of time as compared to the efficacy of administering to a subject an immediate impact treatment alone.

25. An anti-depressive composition comprising ketamine or pharmaceutically acceptable salts thereof, and between about 10 mg and 100 mg D-cycloserine.

26. A kit for use in treating a patient with depression comprising: a) a composition suitable for administration to a patient comprising D- cycloserine; b) a composition suitable for administration to a patient comprising ketamine or the pharmaceutically acceptable salts thereof; and c) instructions for use.