MXPA05003152A - Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines. - Google Patents

Abstract

The invention features a method for treating a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder by administering an SSRI or analog or metabolite thereof and, optionally, a corticosteroid or other compound to the patient. The invention also features a pharmaceutical composition containing an SSRI or analog or metabolite thereof and a corticosteroid or other compound for the treatment or prevention of an immunoinflammatory disorder.

Description

METHODS AND REAGENTS FOR THE TREATMENT OF ASSOCIATED DISEASES AND DISORDERS WITH INCREASED LEVELS OF PRO-INFLAMMATORY CITOOUINS Background of the Invention The invention relates to the treatment of immune-inflammatory disorders. : Immune-inflammatory disorders are characterized by the inappropriate activation of the immune defenses of the body. Instead of attacking infectious invaders, the immune response attacks and damages the tissues of the transplanted body or tissues. The tissue attacked by the immune system varies with the disorder. For example, in multiple sclerosis, the immune response is directed against neuronal tissue, whereas in Crohn's disease, the digestive tract is attacked. The immuno-inflammatory disorders affect millions of individuals and include conditions such as asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, emolytic anemia, inflammatory dermatosis, inflammatory bowel disorders or gastrointestinal (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritis / inflmation, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus Current treatment regimens for immuno-inflammatory disorders typically depend on immunogenic agents The effectiveness of these agents may vary and their use is frequently accompanied by adverse side effects, Thus, improved therapeutic agents and methods for the treatment of immuno-inflammatory disorders are necessary.Compendium of the Invention In one aspect, the invention presents a composition that includes an inhibitor of r selective serotonin e-uptake (SSRI) (or an analogue or metabolite thereof) and a corticosteroid in amounts which together are 'sufficient' to treat an immuno-inflammatory disorder in a patient in need thereof: The composition may include one or more additional compounds (e.g., a glucocorticoid'ei NSAID receptor modulator, COX-2 inhibitor, DMARD, biological, xanthine, anti-cholinergic compound, Beta-receptor agonist, bronchodilator, non-steroidal calcinase inhibitor, vitamin D analogue, psoralen, retinoid, or 5-amino salicylic acid). The composition can be formulated, for example, for topical administration or systemic administration. In another aspect, the invention features a method for decreasing the secretion or production of pro-inflammatory cytokine in a patient by administering to the patient an SSRI, or an analog or metabolite thereof, and a corticosteroid simultaneously or within of 14 days between them in sufficient quantities to decrease the secretion or production of pro-inflammatory cytokine in the patient. In a related aspect, the invention features a method for treating a patient diagnosed with or at risk of developing an immuno-inflammatory disorder by administering to the patient an SSRI, or an analog or metabolite thereof, and a corticosteroid simultaneously or within 14 days between them in sufficient quantities to treat the patient. In any of the above methods, one or more additional compounds may also be administered to the patient (e.g., a glucocorticoid receptor modulator, NSAID, COX- ^ 2 inhibitor, DMÁ.RD, biological, xa tiria, ' 1 anti-cholinergic compound, beta-receptor agonist, "bronchodilator, non-steroidal calcineurin inhibitor, vitamin D analogue, psoralen," retinoid, or 5-salicylic amyloid acid. ·! If desired, the SSRI and / or 'corticosteroid can be administered in a low dose or a high dose. Medications are desirably administered within "10 days of each other, more desirably within five days I entered yes, and even more desirable-" within twenty-four hours I entered yes or even simultaneously (ie concomitantly). "- 'In a related aspect, the invention presents a method for treating an immuno-inflammatory disorder in a patient in need thereof by concomitantly administering to the patient an SSRI (or an analog or metabolite thereof) and a cortico-steroid in amounts which together are more effective in treating the immune-inflammatory disorder than the administration of the corticosteroid in the absence of the SSRI In yet another related aspect, the invention presents a method for treating an immuno-inflammatory disorder in a patient in need thereof by means of concomitantly with the patient an SSRI (or an analog or metabolite thereof) and a cortico-steroid in amounts that together are more effective in treating the immune-inflammatory disorder than the administration of the SSRI in the absence of the corticosteroid. , the invention presents a method for treating an immuno-inflammatory disorder in a patient in need thereof by means of admin. isolate cortico-steroid uri to said patient; and administering an SSRI (or analogous urine or metabolite thereof) to the patient; where: (i) the corticosteroid and the SSRI are administered concomitantly and (ii) the respective amounts of corticosteroid and SSRI administered to the patient are more effective in treating the immune-inflammatory disorder compared with corticosteroid administration in the absence of SSRI or SSRI administration in the absence of corticosteroid. The invention also features a pharmaceutical composition in unit dosage form, the composition including a corticosteroid; and an SSRI or an analogue or metabolite thereof, wherein the amounts of the corticosteroid and the SSRI, when administered to said patient, are more effective in treating the immune-inflammatory disorder compared to the administration of the corticosteroid in the absence of the SSRI or SSRI administration in the absence of corticosteroid. The invention also features a kit that includes (i) a composition that includes an SSRI, or an analog or metabolite thereof, and a corticosteroid; and (ii) instructions for administering the composition to a patient diagnosed with an immuno-inflammatory disorder. In a related aspect, the invention features a kit that includes: (i) an SSRI (or an analog or metabolite thereof), - (ii) a cortico-steroid; and (iii) instructions for administering SSRI and corticosteroid to a patient diagnosed with an immuno-inflammatory disorder. If so, the corticosteroid can be replaced in the methods, compositions, and kits of the invention with a glucocorticoid receptor modulator or other steroid receptor modulator. Thus, in another aspect, the invention features a composition that includes an SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator in amounts that together are sufficient to treat an immuno-inflammatory disorder in a patient in need. of it. If desired, the composition may include one or more additional compounds. The composition may be formulated, for example, for topical administration or systemic administration.

In another aspect, the invention features a method for decreasing secretion or production of pro-inflammatory cytokine in a patient by administering to the patient an SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator simultaneously or within of 14 days to each other in sufficient quantities to decrease secretion or production of pro-inflammatory cytokine in the patient. In another aspect, the invention features a method for decreasing proinflammatory cytokine secretion or production in a patient by administering to the patient an SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator simultaneously or within G4 'days we entered in sufficient quantities to decrease' secretion 'or pro-inflammatory cytokine production in the patient. In a related aspect, the invention presents a method for treating a diagnosed patient. with, or at risk of developing, an immune-inflammatory disorder by administering to the patient an SSRI (or an analogue or metabolite thereof) and a glucocorticoid receptor modulator simultaneously or within 14 days of each other in amounts sufficient to treat the patient.Drugs are desirably administered within 10 days of each other, most desirably within five days of each other, and even more desirably of ntro of twenty-four hours between themselves or even simultaneously (that is) concomitantly).

In a related aspect, the invention presents a method for treating an immuno-inflammatory disorder in a patient in need of the same by means of concomitantly administering to the patient an SS I, or an analogue or metabolite thereof, and a receptor modulator. glucocorticoid in amounts that together are more effective in treating the immune-inflammatory disorder than the administration of the glucocorticoid receptor modulator in the absence of SSRI. In yet another related aspect, the invention features a method for treating an immuno-inflammatory disorder in a patient in need thereof by concomitantly administering to the patient an SSRI., or an analogue or metabolite thereof, and a glucocorticoid receptor modulator in amounts that together are more effective in treating the immune-inflammatory disorder than the administration of SSRI in the absence of the glucocorticoid receptor modulator. In still another related aspect, the invention presents a method for treating an immuno-inflammatory disorder in a patient in need thereof by administering a glucocorticoid receptor modulator to said patient; and administering an SSRI (or an analog or metabolite thereof) to the patient; where: (i) the glucocorticoid receptor modulator and the SSRI are administered concomitantly and (ii) the respective amounts of the glucocorticoid receptor modulator and the SSRI administered to the patient are more effective in treating the immune-inflammatory disorder compared with the administration of the glucocorticoid receptor modulator in the absence of the SSRI or the administration of the SSRI in the absence of the glucocorticoid receptor modulator. The invention also features a pharmaceutical composition in unit dosage form, the composition comprising a glucocorticoid receptor modulator; and an SSRI or an analogue or metabolite thereof, wherein the amounts of the glucocorticoid receptor modulator and the SSRI, when administered to said patient, are more effective in treating the immuno-inflammatory disorder compared to - the administration of the receptor modulator. glucocorticoid in the absence of SSRI or 'administration of SSRI in the absence of the glucocorticoid receptor modulator. "'' | '· |" -. The invention also features a kit that includes (i) a composition that includes an SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator; and (ii) instructions for administering the composition to a patient diagnosed with an immuno-inflammatory disorder. In a related aspect, the invention features a kit that includes: (i) an SSRI, or an analog or metabolite thereof; (ii) a glucocorticoid receptor modulator; and (iii) instructions for administering the SSRI and the glucocorticoid receptor modulator to a patient diagnosed with an immuno-inflammatory disorder.

As described herein, an SSRI, or an analog or metabolite thereof, in the absence of a corticosteroid also has anti-inflammatory activity. Thus, the invention also provides a method for suppressing the secretion of one or more pro-inflammatory cytokines in a patient in need thereof by administering to the patient an SSRI in an amount sufficient to suppress the secretion of pro-inflammatory cytokines in the patient. patient. In a related aspect, the invention features a method for treating a patient diagnosed with an immuno-inflammatory disorder by administering to the patient an SSRI (or an analog or metabolite thereof) in an amount and for a duration sufficient to treat the patient. patient. The invention also features a ki't that includes (i) an SSRI (or an analog or metabolite thereof) and (ii) instructions for administering the SSRI to a patient diagnosed with an immuno-inflammatory disorder. In another aspect, the invention features a pharmaceutical composition that includes an SSRI (or an analog or metabolite thereof) and a second compound selected from the group consisting of a xanthine, anti-cblinergic compound, beta receptor agonist, bronchodilator, inhibitor of non-steroidal calcineurin, vitamin D analogue, psoralen, retinoid, and 5-amino salicylic acid. The invention also features a method for identifying -car combinations of compounds useful for suppressing the secretion of pro-inflammatory cytokines in a patient in need of such treatment by: (a) contacting cells in vitro with an SSRI (or an analog or metabolite thereof) and a candidate compound; and (b) determining whether the combination of SSRI and the candidate compound reduces cytokine levels in blood cells stimulated to secrete cytokines relative to cells contacted with the SSRI but not contacted with the candidate compound or cells. placed in contact with the candidate compound but not placed in contact with the SSRI, where a reduction in cytokine levels identifies the combination as a combination that is useful for treating a patient in need of such treatment. Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, ester salts, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described in the present. By "SSRI" is meant any member of the class of compounds that (i) inhibits serotonin uptake by central nervous system neurons, (ii) has an inhibition constant (Ki) of 10 nM or less, and (iii) ) a selectivity for serotonin over norepinephrine (ie, the ratio of Ki (norepinephrine) to Ki (serotonin)) of more than 100. Typically, SSRIs are administered in doses of more than 10 mg per day when used as anti-depressants. Exemplary SSRIs for use in the invention are described herein. By "cortico-steroid" is meant any compound of natural or synthetic occurrence characterized by a ring system of hydrogenated cyclopentanehydrophenanthrene and having immunosuppressant and / or anti-inflammatory activity. Cortico-steroids that occur naturally are usually produced by the adrenal cortex. Cortico-synthetic steroids can be halogenated. Examples of corticosteroids are provided herein. By "non-steroidal immunophilin-dependent immuno-suppressants" or "NsIDI" is meant any non-steroidal agent which decreases the production or secretion of pro-inflammatory cytokine, binds an immuno-phylline, or causes a down-regulation of the pro-inflammatory reaction. -inflammatory NsIDIs include calcineurin inhibitors, such as cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well as other agents (peptides, peptide fragments)., chemically modified peptides, or peptide mimetics) that inhibit the phosphatase activity of calcineurin. NsIDIs also include rapamycin (sirolimus) and everolimus, which bind to a protein that binds to FK506, FKBP-12, and blocks white blood cell antigen-induced proliferation and cytokine secretion. A "low dose" means at least 5% less (eg, at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest recommended standard dose of a particular compound formulated for a given administration route for treatment of any human disease or condition. For example, a low dose of corticosteroid formulated for administration by inhalation will differ from a low dose of corticosteroid formulated for oral administration. A "high dose" means at least 5% (eg, at least 10%, 20%, 50%, 80%, 90%, or even 95%) more than the highest recommended standard dose of a Particular compound for treatment of any disease or human condition. A "moderate dose" means the dose between the low dose and the high dose. By a "dose equivalent to a dose of prednisolone" is meant a dose of a corticosteroid which, in combination with a given dose of an SSRI, or an analog or metabolite thereof, produces the same anti-inflammatory effect in a patient as a dose of prednisolone in combination with that dose. By "treating" is meant administering or prescribing a pharmaceutical composition for the treatment or prevention of an immuno-inflammatory disease. By "patient" is meant any animal (eg, a human). Other animals that can be treated using the methods, compositions, and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cows, fish , and birds. In one embodiment of the invention, the patient subject to a treatment described herein does not have a clinical depression, anxiety or panic disorder, obsessive / compulsive disorder, alcoholism, eating disorder, attention deficit disorder, personality disorder. borderline, sleep disorder, headache, premenstrual syndrome, irregular heart rhythm, schizophrenia, Tourette syndrome, or phobias. By "a sufficient amount" is meant the amount of a compound, in a combination of the invention, required to treat or prevent an immuno-inflammatory disease in a clinically relevant manner. A sufficient amount of an active compound used to practice the present invention for therapeutic treatment of conditions caused by or contributing to an immuno-inflammatory disease varies depending on the manner of administration, age, body weight, and general health of the patient. Finally, the preceptors will decide the appropriate quantity and dose regime. Additionally, an effective amount may be that amount of the compound in the combination of the invention that is safe and effective in the treatment of a patient having the immuno-inflammatory disease on each agent only as determined and approved by a regulatory authority (such as the Food and Drug Administration of the United States).

By "more effective" it is understood that a treatment exhibits greater efficacy, or is less toxic, safer, more convenient, or less expensive than another treatment with which it is being compared. The efficiency can be measured by a person skilled in the art using any standard method that is appropriate for a given indication. The term "immune-inflammatory disorder" encompasses a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory dermatoses. Immune-inflammatory disorders result in the destruction of healthy tissue by an inflammatory process, deregulation of the immune system, and unwanted proliferation of cells. Examples of immune-inflammatory disorders are acne vulgaris; acute respiratory distress syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammatory diseases, small vessel vasculitis associated with ANCA; ankylosing spondylitis; arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease, Bell's facial paralysis; bullous pemphigoid; cerebral ischemia; chronic obstructive pulmonary disease; Cogan syndrome; contact dermatitis; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis; Mellitus diabetes; discoid lupus erythematosus; eosinophilic fasciitis; erythema nodosum; exfoliative dermatitis; fibromyalgia; focal glomerulosclerosis; giant cell arteritis; drop; gouty arthritis; graft versus host disease; hand eczema; Henoch-Schonlein purple; herpes gestationis; hirsutism; idiopathic cerato-scleritis; Inflammatory bowel or gastrointestinal disorders, inflammatory dermatoses; lichen planus; lupus nephritis; lymphomatous tragueobronchitis; macular edema; multiple sclerosis; myasthenia gravis; myositis; osteoarthritis; pancreatitis; pemphigoid gestationis; vulgar pemphigus; polyarteritis nodosa; Polymyalgia rheumatica; pruritus scroti; Pruritis / inflammation, psoriasis; psoriatic arthritis; rheumatoid arthritis; redidivating polychondritis; rosacea caused by sarcoidosis, - rosacea caused by scleroderma; Rosacea caused by Sweet's syndrome; Rosacea caused by systemic lupus erythematosus; rosacea caused by urticaria; Rosacea caused by pain associated with zoster; sarcoidosis; scleroderma; Segmental glomerulosclerosis; septic shock syndrome; tendinitis or shoulder bursitis; Sjogren's syndrome; Still's disease; brain cell death induced by infarction; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu arteritis; Temporal arteritis; toxic epidermal necrolysis; tuberculosis; Diabetes type 1; Ulcerative colitis; uveitis; vasculitis; and Wegener's granulomatosis. "Non-dermal inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

"Dermal inflammatory disorders" or "inflammatory dermatoses" include, for example, psoriasis, acute febrile neutrophilic dermatosis, eczema (e.g., asteatotic eczema, dyshidrotic eczema, vesicular palmoplantar eczema), balanitis circumscripta plasmacellularis, balanoposthitis, Behcet's disease, Centrifugal annular erythema, persistent dyschromic erythema, erythema multiforme, annular granuloma, clear lichen, lichen planus, lichen sclerosus and atropic, chronic lichen simplex, spinous lichen, nummular dermatitis, pyoderma gangrenosum, sarcoidosis, sub-corneal pustular dermatosis, urticaria, and dermatosis Transitional acantholytic. By "proliferative skin disease" is meant a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of skin proliferative diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperceratosis, premalignant ceratosis, acne, and seborrheic dermatitis. As will be appreciated by a person skilled in the art, a disease, disorder, or particular condition, may be characterized as being both a proliferative skin disease and an inflammatory dermatosis. An example of such a disease is psoriasis.

By "substantial release" or "controlled release" is meant that the therapeutically active component is released from the formulation at a controlled rate such that blood levels therapeutically beneficial (but below toxic levels) of the component and are maintained on a extended period of time varying from v.gr. , about 12 to 24 hours, well, providing, for example, a 12 hour or 24 hour dose form. In generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g. , an alkyl group containing 1 to 7 carbon atoms or 0 to 7 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer numbers of atoms within the specific range. For example, an alkyl group of 1 to 7 carbon atoms includes each of C17 C2, C3, C4, Cs, Cs, and C7. A heteroalkyl 0? _7, for example, includes from 1 to 7 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms can be indicated in a similar way. By "acyl" is meant a chemical moiety with the formula R-C (O) -, where R is selected from 0_7 alkyl, C2_7 alkenyl! C2.7 alkynyl, C2_6 heterocyclic, Cs_12 aryl, Cv alkylaryl 14, C3_10 heterocyclic alkyl, or C ^ heteroalkyl. By "alkoxy" is meant a chemical substituent of the formula -OR, wherein R is selected from C ^ alkyl, C2_7 alkenyl, C2.7 heterocyclic C2_6 alkynyl, Cs.12 aryl / C7_ alkylaryl, C3_10 heterocyclic alky, or heteroalkyl 0a_7. By "aryloxy" is meant a chemical substituent of the formula -OR, where R is a C6_12 aryl group. By "C6.12 aryl" is meant an aromatic group having a ring system comprised of carbon atoms with conjugated n-electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. The aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group can be substituted or unsubstituted. Exemplary substituents include alkyl, idroxide, alkoxide, aryloxide, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups. By "amido" is meant a chemical substituent of the formula -NRR ', wherein the nitrogen atom is part of the amido bond (e.g., -C (O) NRR') and where R and R 'are each, independently, selected from Cx_7f alkyl C2_7 alkenyl / C2_7 alkynyl, heteroaryl Ca_6, aryl Cs_12, alkylaryl C7.14, alk-heterocyclic C3_10, or heteroalkyl C ^, or -NRR 'forms a heterocyclic ring Ca.s, as is defined above, but containing at least one nitrogen atom, such as piperidino, morpholino, and azabicyclo, among others. By "halide" or "halo" is meant bromine, chlorine, iodine, or fluorine. The term "pharmaceutically acceptable salt" means those salts that are, within the scope of sound medical judgment, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are proportional to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in itself during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include salts of acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camforate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfonate, ethanesulfonate, fumarate, glucoheptonate, flicerophosphate, hemisulfate , heptonate, hexanoa-to, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulphonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate. sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers. of the compounds described herein. As an example, by "paroxetine" is meant the free base, as well as any pharmaceutically acceptable salt thereof (e.g., paroxetine maleate, paroxetine hydrochloride hemihydrate, and paroxetine mesylate). Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Detailed Description The invention features methods, compositions, and kits for the administration of an effective amount of an SSRI or analog or metabolite thereof, either alone or in combination with a corticosteroid or other compound to treat immuno-inflammatory disorders. In one embodiment of the invention, the treatment of an immuno-inflammatory disorder is carried out by means of administering an SSRI (or analogue thereof) and a corticosteroid to a patient in need of such treatment. The invention is described in greater detail below. Selective Serotonin Reuptake Inhibitors The methods, compositions, and kits of the invention employ an SSRI, or a structural or functional analog thereof. Suitable SSRIs include cericlamine (e.g., cericlamine idrochloride); citalopram (e.g., citalopram hydrobromide); clovoxamine; cyanodotiepine; dapoxetine; escitalopram (escitalopram oxalate); femoxetine (e.g., femoxetine hydrochloride); fluoxetine (e.g., fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride); indeloxazine (e.g., indeloxazine hydrochloride); Litoxetine; milnacipran (e.g., minlacipran hydrochloride); paroxetine (e.g., paroxetine hydrochloride hemihydrate, paroxetine maleate, paroxetine mesylate); sertraline (e.g., sertraline hydrochloride); tametralin hydrochloride; vicualina; and zimeldin (e.g., zimeldin hydrochloride). Cericlamina Cericlamina has the following structure: Structural analogues of cericlamine are those having the formula: as well as pharmaceutically acceptable salts thereof, wherein j is an alkyl and R 2 is H or C 1-4 alkyl, R 3 is H, alkyl Cj.4, C2_4 alkenyl, phenylalkyl or cycloalkyl with 3 to 5 cyclic carbon atoms, alkanoyl, phenylalkanyl or cycloalkylcarbonyl having 3 to 6 cyclic carbon atoms, or R2 and R3 form, together with the nitrogen atom to which they are attached. bound, a saturated heterocycle with 5 to 7 chain bonds that may have, as the second heteroatom not directly connected to the nitrogen atom, an oxygen, a sulfur or a nitrogen, the last nitrogen heteroatom possibly carrying an alkyl Structural analogues of cericlamin examples are 2-methyl-2-amino-3- (3,4-dichlorophenyl) -propanol, 2-pentyl-2-amino-3- (3,4-dichlorophenyl) -propanol, 2-methyl-2-methylamino- 3 - (3,4-dichlorophenyl) -propanol, 2-methyl-2-dimethylamino-3- (3,4-dichlorophenyl) -propanol, and pharmaceutically acceptable salts of any of them. Citalopram Citalopram has the following structure: Structural analogues of citalopram are those having the formula: as well as their pharmaceutically acceptable salts, wherein each of R a and R 2 are independently selected from the group consisting of bromine, chlorine, fluoro, trifluoromethyl, cyano and R-CO-, wherein R is C 1-4 alkyl. Exemplary structural analogs of citalopram (which are thus structural analogs of SSRI according to the invention) are 1- (4'-fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophthalan; 1- ('-chlorophenyl) -1- (3-dimethylaminopropyl) -5-chlorophthalan; 1- (4 '-bromophenyl) -1- (3-dimethylaminopropyl) -5-chlorophthalane; 1- (4 '-fluorophenyl) -1- (3-dimethylaminopropyl) -5-chlorophthalan; 1 ~ (41-chlorophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-talane; 1- (41-bromo-phenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-phthalane; 1- (4 '-fluorophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-phthalane; 1- (41-fluorophenyl) -1- (3-dimethylaminopropyl) -5-fluorophthalane; 1- (41-chlorophenyl) -1- (3-dimethylaminopropyl) -5-fluoroftalane; 1- (1-chlorophenyl) -1- (3-dimethylaminopropyl) -5-phthalancarbonitrile; 1- (4'-fluorophenyl) -1- (3-dimethylaminopropyl) -5-phthalancarbonitrile; 1 (4'-cyanophenyl) -1- (3-dimethylaminopropyl) -5-phthalancarbonitrile; 1 (41-cyanophenyl) -1- (3-dimethylaminopropyl) -5-chlorophthalane; 1- (41-cyanophenyl) -1- (3-dimethylaminopropyl) -5-trifluoromethyl-phthalane; 1 (4 '-fluorophenyl) -1- (3-dimethylaminopropyl) -5-phthalancarbonitrile 1- (' -chlorophenyl) -1- (3-dimethylaminopropyl) -5-ionylphthalane; 1- (41-chlorophenyl) -1- (3-dimethylaminopropyl) -5-propionylphthalane; and pharmaceutically acceptable salt of any of them. Clovoxamine Clovoxamine has the following structure: Structural analogues of clovoxamine are those having the formula: as well as their pharmaceutically acceptable salts, where Hal is a chloro, bromo, or fluoro group and R is a cyano, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethoxy, or cyanomethyl group. Exemplary structural clovoxamine analogs are 4'-chloro-5-ethoxrvalerophenone 0- (2-aminoethyl) oxime; 41-chloro-5- (2-methoxyethoxy) allerphenone O- (2-aminoethyl) oxime; 4'-chloro-6-methoxycaprofenone O- (2-aminoethyl) oxime; 4 'chloro-6-ethoxycaprofenone O- (2-aminoethyl) oxime; 4'-bromo-5- (2-methoxyethoxy) allerphenone O- (2-aminoethyl) oxime; 4'-bromo-5-methoxivalerophenone O- (2-aminoethyl) oxime; 4'-chloro-6-cyanocaprofenone 0- (2-aminoethyl) oxime; 41 -chloro-5-cianovalerophenone 0- (2-aminoethyl) oxime; 41-bromo-5-cianovalerophenone O- (2-aminoethyl) oxime; and pharmaceutically acceptable salts of any of them. Femoxetine Femoxetine has the foing structure: Structural analogues of femoxetine are those having the formula: where Rx represents a C4_4 alkyl or C2_4 alkynyl group, or a phenyl group optionally substituted by C4_4alkyl, C1_4alkylthio, C4_4alkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulphonyl, methylenedioxy, or tetrahydronaphthyl, R2 represents a C2_4 alkyl or alkynyl group, and R3 represents hydrogen, C- ^ alkyl, Ca_4 alkoxy, trifluoroalkyl, hydroxy, bromo, chloro, fluoro, methylthio, or aralkyloxy. Exemplary structural analogues of femoxetine are disclosed in Examples 7-67 of US Patent 3,912,743, incorporated herein by reference. Fluoxetine Fluoxetine has the foing structure: Structural analogues of fluoxetine are those compounds having the formula: as well as their pharmaceutically acceptable salts, wherein each Rx is independently hydrogen or methyl; R is naphthyl or wherein each of R2 and R3 is independently bromine, chlorine, fluoro, trifluoromethyl, C1-3 alkoxy alkyl or C3.4 alkenyl; and each of n and m is, independently, 0, 1 or 2. Where R is naphthyl, it can be either α-naphthyl or β-naphthyl. Exemplary structural fluoxetine analogs are 3- (p-isopropoxyphenoxy) -3-phenylpropylamine methanesulfonate, N, N-dimethyl 3- (31-4'-dimethoxyphenoxy) -3-phenylpropylamine p-hydroxybenzoate, N, N- bromide dimethyl 3- (a-naphthoxy) -3-phenylpropylamine, N, N-dimethyl 3- (ß-naph-oxy) -3-phenyl-1-methylpropylamine iodide, 3- (2'-methyl-4 '- nitrate) 51-dichlorophenoxy) -3-phenylpropyl mine, 3- (pt-butylphenoxy) -3-phenylpropylamine glutarate, N-methyl 3- (2'-chloro-p-tolyoxy) -3-phenyl-1-methylpropylamine lactate, 3- (2'-4'-dichlorophenoxy) -3-phenyl-2-methylpropylamine citrate, N, N-dimethyl 3- (m-anisoyloxy) -3-phenyl-1-methylpropylamine maleate, N-methyl sulfate 3- (p-Tolioxy) -3-phenylpro-phenylamine, 2,4-dinitrobenzoate of?,? - dimethyl 3- (2 ', 4'-difluorophenoxy) -3-phenylpropylamine, dihydrogenated phosphate of 3- (o-ethylphenoxy) ) -3-phenylpropylamine, N-methyl 3- (2'-chloro-4'-isopropylphenoxy) -3-phenyl-2-methylpropylamine maleate, N, N-dimethyl 3- (21-alkyl-4'-fluoxy) succinate rofenoxi) -3-phenyl-propylamine, N, N-dimethyl 3- (o-isopropoxyphenoxy) -3-phenylpropylamine phenylacetate,?,? -dimethyl 3- (o-brotenophenoxy) -3-phenyl-propylamine-phenylpropionate , N-methyl 3- (p-iodophenoxy) -3-phenyl-propylamine propiolate, and N-methyl 3- (3-n-propylphenoxy) -3-phenyl-propylamine decanoate.

Fluvoxamine Fluvoxamine has the foing structure: Structural analogues of fluvoxamine are those having the formula: as well as their pharmaceutically acceptable salts, wherein cyano, cyanomethyl, methoxymethyl, or ethoxymethyl. Indalpina Indalpina has the foing structure: Structural analogues of indalpine are those having the formula: or their pharmaceutically acceptable salts, where R ± is a hydrogen atom, a Cl-C4 alkyl group, or an aralkyl group of which the alkyl has 1 or 2 carbon atoms, R 2 is hydrogen, C 1-6 alkoxy 0,44 alkyl or alkylthio 0? _4, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy, or amino, the latter optionally substituted by one or two C ^ alkyl groups, an acyl group or an alkylsulfonyl group C-, ^ A represents a -C0 group or -CH2-; and n is 0, 1 or 2. Exemplary structural analogues of indalpine are indolyl-3 (piperidyl-4-methyl) ketone; (methoxy-5-indolyl-3) (piperidyl-4-methyl) ketone; (chloro-5-indolyl-3) (piperidyl-3-methyl) ketone; (indolyl-3) -1 (piperidyl-) -3-propanone, indolyl-3-piperidyl-4-ketone; (methyl-1 indolyl-3) (piperidyl-4-methyl) ketone; (benzyl-1 indolyl-3) (piperidyl-4-methyl) ketone; [(methoxy-5 indolyl-3) -2-ethyl] -piperidine, [(methyl-1-indolyl-3) -2-ethyl] -4-piperidine; [(indolyl-3) -2ethyl] -4 piperidine; (indolyl-3-methyl) -4-piperidine, [(chloro-5-indolyl-3) -2-ethyl] -4-piperidine; [(indolyl-b 3) -3 propyl] -4 piperidine; [(benzyl-1 indolyl-3) -2-ethyl] -4-piperidine; and pharmaceutically acceptable salts of any of them. Indeloxazine Indeloxazine has the following structure: Structural analogues of indeloxazine are those having the formula: and their pharmaceutically acceptable salts, wherein R x and R 3 each represent hydrogen, C 1-4 alkyl or phenyl; R2 represents hydrogen, C4 alkyl, C4.7 cycloalkyl, phenyl, or benzyl; one of the dotted lines means a simple link and the other means a double bond, or its tautomeric mixtures. Exemplary structural analogs of indeloxazine are 2- (7-indenyloxymethyl) -4-isopropylmorpholine; 4-butyl-2- (7-indenyloxymethyl) morpholine; 2- (7-indenyloxymethyl) -4-methylmorpholine; 4-yl -2- (7-indenyloxymethyl) morpholine; 2- (7-indenyloxymethyl) -morpholine; 2- (7-indenyloxymethyl) -4-propylmorpholine; 4-cyclohexyl-2 - (7-indenyloxymethyl) morpholine; 4-benzyl-2- (7-indenyloxymethyl) morpholine; 2- (7-indenyloxymethyl) -4-phenyl morpholine; 2- (4-indenyloxymethyl) morpholine; 2- (3-methyl-7-indenyloxymethyl) -morpholine; 4-isopropyl-2- (3-methyl-7-indenyloxymethyl) morpholine; 4-isopropyl-2- (3-methyl-4-indenyloxymethyl) morpholine; 4-isopropyl-2- (3-methyl-5-indenyloxymethyl) morpholine; 4-isopropyl-2- (l-methyl-3-phenyl-6-indenyloxymethyl) morpholine; 2- (5-indenyloxymethyl) -4-isopropyl morpholine; 2- (6-indenyloxymethyl) -4-isopropyl morpholine; and 4-isopropyl-2- (3-phenyl-6-indenyloxymethyl) morpholine; as well as pharmaceutically acceptable salts of any of them. ilnacipram Milnacipram has the following structure: Structural analogues of milnacipram are those having the formula: as well as their pharmaceutically acceptable salts, wherein each R, independently, represents hydrogen, bromine, chlorine, fluoro, C 1 alkyl, C 1 alkoxy, hydroxy, nitro or amino; each of R and R2, independently, represents hydrogen, C ^ alkyl, C6_12 aryl or C7_14 alkylaryl, optionally substituted, preferably in para position, by bromine, chlorine, or fluoro, or Rx and R2 together form a heterocycle having 5 or 6 members with adjacent nitrogen atoms; R3 and R4 represent hydrogen or an alkyl group C1.i or R3 and R4 form with an adjacent nitrogen atom an etherocycle having 5 or 6 members, optionally containing an additional heteroatom selected from nitrogen, sulfur, and oxygen. Exemplary structural analogues of milnacipram are 1-phenyl-1-aminocarbonyl-2-dimethylaminomethyl-cyclopropane; 1-phenyl-1-dimethylaminocarbonyl 2-dimethylaminomethyl-cyclopropane; 1-phenyl-1-ethylaminocarbonyl 2-dimethylaminomethyl-cyclopropane; 1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane; 1-phenyl-2-dimethylaminomethyl N- (1-chlorophenyl) cyclopropane carboxamide; 1-phenyl-2-dimethylaminomethyl N- (4'-chlorobenzyl) cyclopropane carboxamide; 1-phenyl-2-dimethylaminomethyl N- (2-phenylethyl) cyclopropane carboxamide; (3,4-dichloro-l-phenyl) -2-dimethylaminomethyl N, N-dimethylcyclopropane carboxamide; 1-phenyl-1-pyrrolidino-carbonyl 2-aminomethyl-cyclopropane; 1-orthochlorophenyl-1-aminocarbonyl 2-dimethylaminomethyl-cyclopropane; 1-p-hydroxyphenyl-1-aminocarbonyl-2-dimethylaminomethyl-cyclopropane; 1-p-Nitrophenyl-1-dimethylaminocarbonyl 2-dimethylaminomethyl-cyclopropane; 1-p-aminophenyl-1-dimethylaminocarbonyl 2-dimethylaminomethyl-cyclopropane; 1-p-tolyl-1-methylaminocarbonyl-2-dimethylaminomethyl-cyclopropane; 1-p-methoxyphenyl-1-aminomethylcarbonyl-2-aminomethyl-cyclopropane; and pharmaceutically acceptable salts of any of them. Paroxetine Paroxetine has the following formula: Structural analogs of paroxetine are that having the formula: and their pharmaceutically acceptable salts, wherein l represents hydrogen or an alkyl group Cl-4, and the fluorine atom may be in any of the available positions.

Sertralxna Sertralxna has the following structure: Structural analogs of sertraline are those having the formula: wherein R2 is selected from the group consisting of hydrogen and C1-4 alkyl; R2 is alkyl Ci ?; X and Y are each selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, alkoxy C ^, and cyano; and W is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and C2 alkoxy. Preferred sertraline analogues are in the cis-isomeric configuration. The term cis-isomeric "refers to the relative orientation of the R-JRJ and phenyl portions in the cyclohexene ring (ie, if both are oriented on the same side of the ring.) Because both carbons 1 and 4 are Asymmetrically substituted, each cis- compound has two optically active enantiomeric forms denoted (with reference to carbon 1) as the cis- (IR) and cis- (1S) enantiomers. Particularly useful are the following compounds, in either the (1S ) -enantiomeric or (1S) (IR) racemic, and their pharmaceutically acceptable salts: cis-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; N-methyl-4- (4-bromophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine, cis-N-methyl-4- (4-chlorophenyl) -1,2,3, 4-tetrahydro- l-naphthalenamine; cis-N-methyl-4- (3-trifluoromethyl-phenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; cis-N-methyl-4- (3-trifluoromethyl-4-chlorophenyl) ) -1,2,3, 4-tetrahydro-1-naphthalenamine, cis-M, N-dimethyl-4- (4-chloro) ofhenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; cis-N, -dimethyl-4 - (3-trifluoromethyl-phenyl) -1,2,3,4-tetrahydro-1-naphthalenamine; and cis-N-methyl-4- (4-chlorophenyl) -7-chloro-1,2,3,4-tetrahydro-1-naphthalenamine. Of interest is also the enantiomer (IR) of cis-N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine. Zimeldina Zimeldine has the following structure: Structural analogues of zimeldine are those compounds having the formula: and pharmaceutically acceptable salts thereof, wherein the pyridine nucleus is ligated to ortho-, meta- or para- position to the adjacent carbon atom and where R is selected from the group consisting of H, chloro, fluoro, and bromine . Exemplary zimeldin analogues are (e) - and (γ) - 3- (4'-bromophenyl-3- (2"-pyridyl) -dimethylallylamine; 3- (41-bromo-phenyl) -3- (3" -pyridyl) - dimethylallylamine; 3- (4'-bromo-phenyl) -3- (4"-pyridyl) -dimethylallylamine; and pharmaceutically acceptable salts of any of them." Structural analogues of any of the above SSRIs are considered herein to be SSRI analogs and thus can be used in any of the methods, compositions, and kits of the invention Metabolites Pharmaceutically active metabolites of any of the above SSRIs can also be used in the methods, compositions, and kits of the invention Exemplary metabolites are didesmethylcitalopram, desmethylcitalopram, desmethylsertraline, Analogs Functional analogues of SSRIs can also be used in the methods, compositions, and kits of the invention Exemplary SSRI functional analogs are provided below.A class of SSRI analogs are SNRIs ( selective reuptake inhibitors of norepinephrine serotonin), which include venlafaxine and duloxetine. Venlafaxine Venlafaxine has the following structure: Structural analogues of venlafaxine are those compounds having the formula: as well as their pharmaceutically acceptable salts, where A is a portion of the formula: where the dotted line represents optional unsaturation; ¾ is hydrogen or alkyl; R2 is C1_4 alkyl; R 4 is hydrogen, alkyl formyl or alkanoyl; R3 is hydrogen or C1_4 alkyl; R5 and R5 are, independently, hydrogen, hydroxyl, C1-4 alkyl, alkoxy 0-4, alkanoyloxy 0-4, cyano, nitro, alkylmercapto, amino, alkylamino C2, dialkylamino, alkanoid C4, halo, trifluoro- methyl or, taken together, methylenedioxy, - and n is 0, 1, 2, 3 or 4. Duloxetine Duloxetine has the following structure: Structural analogues of duloxetine are those compounds described by the formula disclosed in US Pat. No. 4,956,388, incorporated herein by reference. Other SSRI analogues are 1,2,3,4-tetrahydro-N-methyl-4-phenyl-1-naphthylamine hydrochloride; 1,2,3,4-tetrahydro-N-methyl-4-phenyl- (E) -1-naphthylamine hydrochloride; N, N-dimethyl-1-phenyl-1-phthalanpropylamine hydrochloride; gamma- (4- (trifluoromethyl) phenoxy) -benzenepropanamine hydrochloride; BP 554; CP 53261; O-desmethylvenlafaxine; WY 45,818; And 45,881; N- (3-fluoropropyl) paroxetine; and Lu 19005.

Recommended Standard Dosage. The recommended standard dosages for exemplary SSRIs are given in Table 1, below. Other standard dosages are provided, e.g., in Merck Manual of Diagnosis & T erapy (17th edition, MH Beers et al, Merck & Co. ) and Physicians' Desk Reference 2003 (57th edition, Medical Economics Staff et al., Medical Economics Co., 2002). Table 1 Corticosteroids If desired, one or more corticosteroids can be administered in a method of the invention or can be formulated with an SSRI, or an analog or metabolite thereof, in a composition of the invention. Suitable cortico-steroids include 11-alpha, 17-alpha, 21-tri idroxipregn-4-ene-3, 20-dione; 11-beta, 16-alpha, 17, 21-tetrahydroxypregn-4-ene-3, 20-dione; 11-beta, 16-alpha, 17, 21-tetrahydroxyprg-1, 4-diene-3, 20-dione; 11-beta, 17-alpha, 21-trihydroxy-6-alpha-methylpregn-4-ene-3, 20-dione; 11-dehydrocorticosterone; 11-deoxycortisol; ll-hydroxy-l, 4-androstadiene-1, 17-dione 11-ketotetosterone; 14-hydroxyandorst-4-ene-3, 6, 17-trione; 15, 17-dihydroxyprogesterone; 16-methylhydro-cortisone; 17, 21-dihydroxy-16-alpha-methylpregna-1,4,9 (11) -triene-3,20-dione; 17-alpha-hydroxyprren-4-ene-3, 20-dione 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta-pregn-9 (11) -eno-3, 20-dione; 17-hydroxy-4,6,8 (14) -pregnatriene-3,20-dione; 17-hydroxypregna-4, 9 (11) -diene-3, 20-dione; 18-hydroxycorticostero-na; 18-hydroxycortisone; 18 -oxocortisol; 21-deoxyaldosterone; 21-deoxycortone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregneno-17-alpha, 20-beta, 21-triol-3, l-dione; 6.17, 20-trihydroxypregn-4-ene-3 -one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 21-acetate 6-alpha-methylprednisolone, sodium salt of 6-alpha-methylprednisolone 21-hemisuccinate, 6-beta-hydroxycortisol, 21-acetate 17-butyrate 6-alpha , 9-alpha-difluoroprednisolone, 6-hydroxycorticosterone; 6-hydroxidesxametasone; 6-hydroxyprednisolone; 9-fluorocortisone; alclometasone dipropionate; aldosterone; algestone; alfader-ma; amadinone; amcinonide; anagestone; androstenedione; anechortava acetate; beclomethasone; Beclomethasone dipropionate; Beclomethasone monohydrate dipropionate; 17-betamethasone valerate, - betamethasone sodium acetate; sodium phosphate of betamethasone; betamethasone valerate; Ballsterone; budesonide; caluesterone; Chlormadinone; chloroprednisone; chloro-prednisone acetate; cholesterol; clobetasol; clobetasol propionate; clobetasone; clocortolone; clocortolone pivalate; clogestone; cloprednol; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cypionate; cortisol octanoate; sodium cortisol phosphate; sodium cortisol succinate; cortisol valerate; cortisone; cortisone acetate; shortdoxona; daturaolone; deflazacort, 21-deoxycortisol, dehydroepi ndrosterone; delmadinone; Deoxycorticosterone; deprodone; descinolone; desonida; deoxymethasone; dexfeno; dexamethasone; 21-dexamethasone acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; difluorasone; difluorasone diacetate; difluocortolon; dihydroelatericin a; domoprednate; doxibet-asol; ecdysone; ecdysterone; endrisone; enoxolone; flucinolone; fludrocortisone; fludrocorti-sona acetate; Flugestone; flumethasone; flumethasone pivalate; flumoxo-nida; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; 9-fluorocortisone; fluocortolone; fluorohydroxy-droestenodion; fluorometholone; fluorometholone acetate; Fluoxymesterone; fluprednidene; fluprednisolone; fluorandrenoli-da; fluticasone; fluticasone propionate; formebolone; formestane; formocortal; gestonorone; gliderinin; Halcinonide; hircanoside; Halometasone; halopredone; haloprogesterone; hydrocortiosone cypionate; hydrocortisone; 21-hydrocortisone butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone probutate; sodium hydrocortisone phosphate; sodium hydrocortisone succinate; hydrocortisone valerate; hydroxyprogesterone; inokoesterone; isofluopredone; isofluopredone acetate; isoprednidene; mechloridane; mecortolon; medroges-tona; medroxyprogesterone; raedrisone; megestrol; Megestrol acetate; melengestrol; meprednisone; Methandrostenolone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; Methylprednisolone Sodium Succinate; methyltestosterone; metribolone; mometasone; Mometasone furoate; mometasone furoate monohydrate; nisone; nomegestrol; norgestomet; norvinysterone; oxymesterone; parametasone; parametasone acetate; ponsteroid; Prednisolylate; prednisolone; 21-prednisolone hemisuccinate; prednisolone acetate; prednisolone farnesylate; prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide); prednisolone metasulfofenzoate; prednisolone sodium phosphate; prednisolone estealate; prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; predni al; prednilidene; pregnenolone; procinonide; tralonida; progesterone; promegestone; rapontesterone; rimexolone; roxibolone; rubrosterone; Stizophylline; tixocortol; topterone; triamcinolone; triamcinolone acetonide; 21-triamcinolone acetonide palmitate; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turquesterone; and ortmanin. Standard recommended dosages for various steroid / disease co-bracings are given in 2, below. Table 2 - Cortico-Steroid Dosages Recommended Standard Standard recommended dosages for corticosteroids are provided, e.g., in Merck Manual of Diagnosis & Therapy (17th edition, MH Beers et al., Merck &Co.) And Physicians' Desk Reference 2003 (57th edition, Medical Economics Staff et al., Medical Economics Co., 2002). In one embodiment, the dose of corticosteroid administered is a dose equivalent to a dose of prednisolone, as defined herein. For example, a low dose of a corticosteroid can be considered as the dose equivalent to a low dose of prednisolone. Modulators Receptors of Steroids Steroid receptor modulators (eg, antagonists and agonists) can be used as a substitute for or in addition to a cortico-steroid in the methods, compositions, and kits of the invention. Thus, in one embodiment, the invention features the combination of an SSRI (or its analog or metabolite) and a glucocorticoid receptor modulator or other steroid receptor modulator, and methods for treating immuno-inflammatory disorders with them. Glucocorticoid receptor modulators that can be used in the methods, compositions, and kits of the invention include compounds described in US Pat. No. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, US Patent Application Publications 2003/0176478, 2003 / 0171585, 2003/0120081, 2003/0073703, 2002/015631, 2002/0147336, 2002/0107235, 2002/0103217, and 2001/0041802, and PCT publication WO 00/66522, each of which is incorporated in the present by reference. Other receptor modulators steroids can also be used in the methods, compositions, and kits of the invention are described in US Patents 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, each of which is incorporated herein by reference. Other Compounds Other compounds that can be used as a substitute for, or in addition to, a corticosteroid in the methods, compositions, and kits of the invention are A-348441 (Karo Bio), adrenal cortex extract (GlaxoSmithKline), alsactide (Aventis), amebucort (Schering AG), amelometasona (Tais o), ATSA (Pfizer), bitolterol (Elan), CBP-2011 (InKine Pharmaceutical), cebaracetam (Novartis) CGP-13774 (Kissei), ciclesonide (Altana) , ciclomethasone (Aventis), clobetasone butyrate (GlaxoSmithKline), cloprednol (Hoffmann-La Roche), collismycin A (Kirin), cucurbitacin E (NIH), deflazacort (Aventis), deprodone propionate (SSP), acefurato dexamethasone (Schering -Plough), dexamethasone linoleate (GlaxoSmithKline), dexamethasone valerate (Abbott), difluprednate (Pfizer), domoprednato (Hoffmann-La Roche), ebiratide (Aventis), etiprednol dicloacetate of (IVAX), fluazacort (Vicuron), flumoxonida ( Hoffmann-La Roche), fluocortin butyl (Schering AG), fluocortolone monohidra-Tada (Schering AG), GR-250495X (GlaxoSmithKline), halometasone (Novartis), halopredone (Dainippon), HYC-141 (Fidia), enbutato of icomethasone (Hovione), itrocinonida (AstraZeneca), L-6485 (Vicuron ), Lipocort (Draxis Health), locicortone (Aventis), meclorisone (Schering-Plow), naflocort (Bristol-Myers Squibb), NCX-1015 (NicOx), NCX-1020 (NicOx), NCX-1022 (NicOx), nicocorto -nide (Yamanouchi), NIK-236 (Nikken Chemicals), NS-126 (SSP), Org-2766 (Akzo Nobel), Org-6632 (Akzo Nobel), P16CM, propylmeste-rolona (Schering AG), RGH-1113 (Gedeon Richter), rofleponide (AstraZeneca), rofleponide palmitate (AstraZeneca), RPR-106541 (Aventis), RU-26559 (Aventis), Sch-19457 (Schering-Plow), T25 (Matrix Therapeutics), TBI-PAB ( Sigma-Tau), ticabesone propionate (Hoffmann-La Roche), tifluadom (Solvay), timobesone (Hoffmann-La Roche), TSC-5 (Takeda), and ZK-73634 (Schering AG). Therapy The invention features methods for suppressing pro-inflammatory cytokine secretion as a means of treating an immuno-inflammatory disorder, proliferative skin disease, rejection of organ transplantation, or graft-versus-host disease. The suppression of cytokine secretion is achieved by means of administering one or more SSRIs in combination, optionally with one or more steroids. Although the examples describe a simple SSRI and a single steroid, it is understood that the combination of multiple agents is often desirable. For example, methotrexate, hydroxychloroquine, and sulfasalazine are commonly administered for the treatment of rheumatoid arthritis. Additional therapies are described below. Chronic Obstructive Pulmonary Disease In one embodiment, the methods, compositions, and kits of the invention are used for the treatment of chronic obstructive pulmonary disease (COPD). If desired, one or more agents typically used to treat COPD can be used as a substitute for, or in addition to, a corticosteroid in the methods, compositions, and kits of the invention. Such agents include xanthines (e.g., theophylline), anticholinergic compounds (e.g., ipratropium, tiotropium), and beta-ta / bronchodilator receptor agonists (e.g., lupolul sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol escetate, salmeterol xinafoate, and terbutaline). Thus, in one embodiment, the invention features the combination of an SSRI (or its analog or metabolite) and a bronchodilator, and methods of treating COPD with them. Psoriasis The methods, compositions, and kits of the invention can be used for the treatment of psoriasis. If desired, one or more anti-psoriatic agents typically used to treat psoriasis may be used as a substitute for, or in addition to, a corticosteroid in the methods, compositions, and kits of the invention. Such agents include biologics (e.g., alefacept, infixamab, adelimumab, efalizumab, etanercept, and CDP-870), non-steroidal calcineurin inhibitors (e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), vitamin analogues D (e.g., calcipotriene, calcipotriol), psoralens (e.g., methoxsalen), retinoids (e.g., acitretin, tazoretena), DMARDs (e.g., methotrexate), and anthralin. Thus, in one embodiment, the invention features the combination of an SSRI (or its analog or metabolite) and an anti-psoriatic agent, and methods of treating psoriasis with them. Inflammatory bowel disease The methods, compositions, and kits of the invention can be used for the treatment of inflammatory bowel disease. If desired, one or more agents typically used to treat inflammatory bowel disease may be used as a substitute for, or in addition to, a corticosteroid in the methods, compositions, and kits of the invention. Such agents include biologics (e.g., inflixamab, adelimumab, and CDP-870), non-steroidal calcineurin inhibitors (e.g., cyclosporin, tacrolimus, pimecrolimus, and ISAtx247), 5-amino salicylic acid (v. ., mesalamine, sulfasalazine, balsalazide disodium, and olsalazine sodium), DMARDs (e.g., methotrexate and azathioprine) and alosetron. Thus, in one embodiment, the invention features the combination of an SSRI (or its analog or metabolite) and any of the above agents, and methods of treating inflammatory bowel disease with them.

Rheumatoid Arthritis The methods, compositions, and kits of the invention can be used for the treatment of rheumatoid arthritis. If desired, one or more agents typically used to treat rheumatoid arthritis may be used as a substitute for, or in addition to, a corticosteroid in the methods, compositions, and kits of the invention. Such agents include NSAIDs (e.g., naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, and tolmetin), COX-2 inhibitors (e.g., rofecoxib, celecoxib, valdecoxib, and lumiracoxib), biological (e.g., inflixamab, adelimumab, etanercept, and CDP-870), non-steroidal calcineurin inhibitors (e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), 5-amino-salicylic acid (e.g., mesalamine, sulfasalazine, disodium balsalazide, and sodium olsalazine), DMARDs (e.g., methotrexate, leflunomide, minocycline, auranofin, gold and sodium thiomalate, aurothioglyco-sa, and azathioprine), hydroxychloroquine sulfate , and penicillamine. Thus, in one embodiment, the invention features the combination of an SSRI (or its analog or metabolite) with any of the above agents, and methods of treating rheumatoid arthritis therewith.

Asthma The methods, compositions, and kits of the invention can be used for the treatment of asthma. If desired, one or more agents typically used to treat asthma can be used as a substitute for, or in addition to, a corticosteroid in the methods, compositions, and kits of the invention. Such agents include beta 2 agonists / bridging / modifiers of leukotriene (e.g., zafirlukast, montelukast, and zileuton), biologics (e.g., omalizumab), anti-cholinergic compounds, xanthines, ephedrine, guaifenesin, cromolyn sodium, sodium medocromil, and deo potassium iodide. Thus, in one embodiment, the invention features the combination of an SS I (or its analog or metabolite) and any of the above agents, and methods of treating asthma with them. Immuno-suppressors Non-Steroidal Immunophilin Depressants In one embodiment, the invention features methods, compositions, and kits employing an SSRI and a non-spheroidal immunophilin-dependent immunosuppressant (NsIDI), optionally with a corticosteroid or other agent described herein. In healthy individuals, the immune system uses cellular effectors, such as B cells and T cells, to attack infectious microbes and abnormal cell types while leaving normal cells intact. In individuals with an autoimmune disorder or a transplanted organ, activated T cells damage healthy tissues. Inhibitors of calcineurin (eg, cyclosporins, tacrolimus, pimecrolimus), and rapamycin attack many types of immune-regulatory cells, including T cells, and suppress the immune response in organ transplantation and autoimmune disorders. Cyclosporins Cyclosporins are fungal metabolites that comprise a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A, and its deuterated analog ISAtx247, and hydrophobic cyclic polypeptide consisting of eleven amino acids. Cyclosporin A binds and forms a complex with the intracellular cyclophilin receptor. The cyclosporin-cyclophilin complex binds to and inhibits calcineurin, a calcium-dependent serine-threonine-specific protein phosphatase Ca2 + -calmodulin. Calcineurin mediates signal transduction events required for T cell activation (reviewed in Schreiber et al., Cell 70: 365-368, 1991). Cyclosporins and their functional and structural analogs suppress the T cell-dependent immune response by inhibiting signal transduction triggered by antigen. This inhibition decreases the expression of pro-inflammatory cytokines, such as IL-2. Many cyclosporins (e.g., cyclosporin A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporin A is commercially available as NEORAL from Novartis. The structural and functional analogs of cyclosporin? include cyclosporins having one or more fluorinated amino acids (described, e.g., in US Patent 5,227,467); cyclosporins having modified amino acids (described, e.g., in US Patents 5,122,511 and 4,798,823); and deuterated cyclosporins, such as ISAtx247 (descorita in the publication of patent application US 2002/0132763). Additional cyclosporin analogues are described in US Patents 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporin analogues include, but are not limited to, D-Sar (oi-SMe) 3 Val2-DH-Cs (209-825), Allo-Thr-2 -Cs, Norvaline-2-Cs, D-Ala (3 -acetylamino) -8-Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-Ser (O-CH2CH2-OH) -8-Cs, and D-Ser-8-Cs, which are describe in Cruz et al (Antimicrob Agents Chemother, 44 ': 143-149, 2000). Cyclosporins are highly hydrophobic and readily precipitate in the presence of water (eg, in contact with body fluids). Methods for providing cyclosporin formulations with improved bioavailability are described in US patents 4,388,307, 6,468,7,968, 5,051,402, 5,342,625, 5,977,066, and 6,022,852. Cyclosporin microemulsion compositions are described in US patents 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and 6,024,978. Cyclosporins can be administered either intravenously or orally, but oral administration is preferred. To counteract the hydrophobicity of cyclosporin A, an intravenous cyclosporin A is usually provided in an ethanol-polyoxyethylated castor oil vehicle that must be diluted prior to administration. Cyclosporin A can be provided, e.g. , as a microemulsion in tablets of 25 or 100 mg, or in an oral solution of 100 mg / ml (NEORAL). Typically, the patient dosage of an oral cyclosporin varies according to the patient's condition, but some standard recommended dosages in treatment regimens of the state of the art are provided herein. Patients undergoing organ transplantation typically receive an initial dose of oral cyclosporin A in amounts between 12 and 15 mg / kg / day. The dose is then gradually decreased by 5% per week until a maintenance dose of 7-12 mg / kg / day is reached. For intravenous administration, 2-6 mg / kg / day is preferred for most patients. For patients diagnosed as having Crohn's disease or ulcerative colitis, dosage amounts of 6-8 mg / kg / day are usually given. For patients diagnosed as having systemic lupus erythematosus, dosage amounts of 2.2-6.0 mg / kg / day are usually given. For psoriasis or rheumatoid arthritis, dosage amounts of 0.5-4 mg / kg / day are typical. Other useful doses include 0.5-5 mg / kg / day, 5-10 mg / kg / day, 10-15 mg / kg / day, 15-20 mg / kg / day, or 20-25 mg / kg / day. Frequently cyclosporins are administered in combination with other immunosuppressive agents, such as glucocorticoids. Additional information is provided in Table 3.

Table 3 - NsIDIs Legend CsA = cyclosporin A RA = rheumatoid arthritis UC = ulcerative colitis SLE = systemic lupus erythematosus Tacrolimus Tacrolimus (PROGRAF, Fujisawa), also known as FK506, is an immunosuppressive agent that attacks intracellular signal transduction pathways of T cells. tacrolimus is linked to an intracellular protein F 506, binding protein, (FKBP-12) that is not structurally related to cyclophilin (Harding et al., Nature 341: 758-7601, 1989; Siekienka et al., Nature 341: 755 -757, 1989 and Soltoff et al., J. Biol. Chem. 267: 17472-17477, 1992). The FKBP / FK506 complex binds to calcineurin and inhibits the phosphatase activity of calcineurin. This inhibition prevents the dephosphorylation and nuclear translocation of NFAT, a nuclear component that initiates the transcription of genes required for the production of lymphokine (e.g., IL-2, gamma-interferon) and the activation of T cells. Thus, tacrolimus inhibits the activation of T cells. Tacrolimus is a macrolide antibiotic that is produced by Streptomyces tsukubaensis. It suppresses the immune system and prolongs the survival of transplanted organs. It is currently available in oral and injectable formulations. Tacrolimus capsules contain 0.5, 1, or 5 mg of anhydrous tacrolimus within a gelatin capsule shell. The injectable formulation contains 5 mg of anhydrous tracrolimus in castor oil and alcohol that is diluted with 9% sodium chloride or 5% dextrose prior to injection. Although oral administration is preferred, patients unable to take oral capsules may receive tacrolimus injection. The initial dose should be administered not earlier than six hours after the transplant by continuous intravenous infusion. Tacrolimus and tacrolimus analogues are described by Tanaka et al., (J. Am. Chem. Soc., 109: 5031, 1987), and in US patents 4,894,366, 4,929,611, and 4,956,352. Compounds related to FK506, including FR-900520, FR-900523, and FR-900525, are described in US patent 5,254,562; O-aryl, 0-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US patents 5,250,678, 532,248, 5,693,648; amino O-aryl macrocrystals are described in US Pat. No. 5,284,840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylheteroaryl macrolides are described in US Pat. No. 5,208,241; aminomacrolides and their derivatives are described in US Pat. No. 5,208,228; fluoromacrolides are described in US Pat. No. 5,189,042; amino O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US patent 5,162,334; and halomacrolides are described in US Pat. No. 5,143,918. Although suggested dosages will vary with the condition of a patient, standard recommended dosages used in treatment regimens of the state of the art are provided below. Patients diagnosed with Crohn's disease or ulcerative colitis are administered with 0.1-0.2 mg / kg / day of oral tacrolimus. Patients having a transplanted organ typically receive doses of 0.1-0.2 mg / kg / day of oral tacrolimus. Patients being treated for rheumatoid arthritis typically receive 1-3 mg / day of oral tacrolimus. For the treatment of psoriasis, 0.01-0.15 mg / kg / day of oral tacrolimus are administered to the patient. Atopic dermatitis can be treated twice a day by applying a cream with 0.03-0.1% tacrolimus to the affected area. Patients receiving oral tacrolimus capsules typically receive the first dose no earlier than six hours after the transplant, or eight to twelve hours after the infusion of intravenous tacrolimus was discontinued. Other suggested tacrolimus dosages include 0.005-0.01, 0.01-0.03, 0.03-0.05, 0.05-0.07, 0.07-0.10, 0.10-0.25, or 0.25-0.5 mg / kg / day. Tacrolimus is extensively metabolized by the mixed-function oxidase system, in particular, by the P-450 cytochrome system. The primary mechanism of metabolism is demethylation and hydroxylation. Although several metabolites of tacrolimus are likely to exhibit immunosuppressive biological activity, the 13-demethyl metabolite is reported to have the same activity as tacrolimus. Pimecrolimus and Ascomycin Derivatives Ascomycin is a close structural analogue of PK506 and is a potent immunosuppressant. It binds to FKBP-12 and suppresses its rotamase proline activity. The ascichicin-FKBP complex inhibits calcineurin, a type 2B phosphatase. Pimecrolimus (also known as SDZ ASM-981) is a 33-epi-chloro derivative of ascomycin. It is produced by the strain Streptomyces hygroscopicus var. ascomyceitus. Like tacrolimus, pimecrolimus (ELIDEL, Novartis) binds to FKBP-12, inhibits calcineurin phosphatase activity, and inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits the production of IL-2 and the release of other pro-inflammatory cytokines. Structural and functional analogs of pimecrolimus are described in US Pat. No. 6,384,073. Pimecrolimus is particularly useful for the treatment of atopic dermatitis. Pimecrolimus is currently available as a 1% cream. Although individual dosage will vary with the patient's condition, some recommended standard dosages are provided below. Oral pimecrolimus can be given for the treatment of psoriasis or rheumatoid arthritis in amounts of 40-60 mg / day. Amounts of 80-160 mg / day of pimecrolimus can be given for the treatment of Crohn's disease or ulcerative colitis. Patients taking an organ transplant can be administered with 160-240 mg / day of pimecrolimus. Patients diagnosed as having systemic lupus erythematosus can be administered with 40-120 mg / day of pimecrolimus. Other useful doses of pimecrolimus include 0.5-5, 5-10, 10-30, 40-80, 80-120, or even 120-200 mg / day. Rapamycin Rapamycin (Rapamune sirolimus, Wyeth) is a cyclic lactone produced by Steptomyces hygroscopicus. Rapamycin is an immunosuppressive agent that inhibits the activation and proliferation of T-lymphocyte. Like the cyclosporins, tacrolimus, and pimecrolimus, rapamycin forms a complex with the immunophilin FKBP-12, but the rapamycin-FKBP-12 complex does not inhibit the activity of calcineurin phosphatase. The rapamycin-immunophilin complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase that is required for cell cycle progression. The inhibition of mTOR kinase activity blocks the proliferation of T-lymphocyte and lymphokine secretion. Structural and functional analogues of rapamycin include mono- and di-acylated rapamycin derivatives (US patent 4,316,885); water-soluble pro-drugs of rapamycin (US Patent 4,650,803); esters of carboxylic acids (PCT publication WO 92/15179); carbamates (US patent 5,118, 678); amide esters (US patent 5,118,678); biotin esters (US patent 5,504,091); fluorinated esters (US patent 5,100,883); hold them (US Patent 5,151,413); Silyl ethers (US patent 5,120,842); bicyclic derivatives (US patent 5,120,725); rapamycin dimers (US patent 5,120,727); O-aryl, O-alkyl, O-alkenyl and 0-alkynyl derivatives (US patent 5,258,389); and deuterated rapamycin (US patent 6,503,921). Additional rapamycin analogs are described in US Patents 5,202,332 and 5,169,851. Everolimus (40-O- (2-hydroxyethyl) rapamycin; CERTICAN; Novartis) is an immunosuppressive macrolide that is structurally related to rapamycin, and has been found to be particularly effective in preventing acute rejection of organ transplantation when given in combination with cyclosporin A. Rapamycin is currently available for oral administration in liquid and tablet formulations. RAPAMUNE liquid contains 1 mg / mL of rapamycin that is diluted in water or orange juice prior to administration. Tablets containing 1 or 2 mg of rapamycin are also available. Rapamycin is preferably given once a day as soon as possible after transplantation. It is absorbed quickly and completely after oral administration. Typically, the dosing of rapamycin patients varies according to the patient's condition, but some recommended standard dosages are provided below. The initial loading dose for rapamycin is 6 mg. Subsequent maintenance doses of 2 mg / day are typical. Alternatively, a loading dose of 3, 5, 10, 15, 20, or 25 mg can be used with a maintenance dose of 1, 3, 5, 6, or 10 mg per day. In patients weighing less than 40 kg, the rapamycin dosages are typically adjusted based on body surface area; generally a loading dose of 3 mg / m2 / day and a maintenance dose of 1 mg / m2 / day are used. Peptide Fractions Peptides, peptide mimetics, peptide fragments, whether natural, synthetic or chemically modified, which impart calcineurin-mediated dephosphorylation and the nuclear translocation of NFAT are suitable for use in the practice of this invention. Examples of peptides that act as calcineurin inhibitors by inhibiting the activation of NFAT and the transcription factor NFAT are described, e.g. , by Aramburu et al., Science 285: 2129-2133, 1999 and Aramburu et al., Mol. Cell 1: 627-637, 1998. As a class of calcineurin inhibitors, these agents are useful in the methods of the invention. Administration In particular embodiments of any of the methods of the invention, the compounds are administered within 10 days to each other, within five days to each other, within twenty-four hours to each other, or simultaneously. The compounds can be formulated together as a single composition, or can be formulated and administered separately. One or both compounds can be administered in a low dose or in a high dose, each of which are defined herein. It may be desirable to administer to the patient other compounds, such as a corticosteroid, NSAID (e.g., naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindaco, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, trisalicylate choline magnesium , sodium salicylate, salicylsalicylic acid, fenopro-pheno, flurbiprofen, ketoprofen, meclofenamate sodium, meloxi-cam, oxaprozin, sulindac, and tolmetin), COX-2 inhibitor (eg, rofecoxib, celecoxib, valdecoxib, and lumiracoxib) ), glucocorticoid receptor modulator, or DMARD. Combination therapies of the invention are especially useful for the treatment of immuno-inflammatory disorders in combination with other anti-cytokine agents or agents that modulate the immune response to positively effect disease, such as agents that influence cell adhesion, or biological agents (ie, agents that block the action of IL-6, IL-1, IL-2, IL-12, IL-15 or TNFa (e.g. , etanercept, adelimumab, inflixi-mab, or CDP-870)). In this example (that of agents that block the effect of TNFOI), combination therapy reduces the production of cytokines, etanercept or infliximab by acting on the remaining fraction of inflammatory cytokines, providing improved treatment. The therapy according to the invention can be carried out alone or in conjunction with another therapy and can be provided at home, the doctor's office, a clinic, an outpatient department of outpatient hospital care, or a hospital. The treatment optionally begins in a hospital so that the doctor can observe the effects of the therapy closely and make any adjustments that may be necessary, or may begin on a basis of external patient care. The duration of the therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of illness of the patient, and how the patient responds to treatment. Additionally, a person having a higher risk of developing an inflammatory disease (e.g., a person who is subject to age-related hormonal changes) may be treated to inhibit or delay the establishment of symptoms. Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (such as intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intra-peritoneal administration , intra-articular, ophthalmic or oral). As used herein, "systemic administration" refers to all non-dermal routes of administration, and specifically excludes routes of topical and transdermal administration. In combination therapy, the dose and frequency of administration of each component of the combination can be controlled independently. For example, a compound can be administered three times per day, while the second compound can be administered once per day. The combination therapy may occur in and out of cycles that include rest periods such that the patient's body has a chance to recover from any side effects not previously anticipated. The compounds can also be formulated together such that one administration delivers both compounds. Formulation of Pharmaceutical Compositions Administration of a combination of the invention can be by any suitable means that results in suppression of pro-inflammatory cytokine levels in the target region. The compound may be contained in any suitable amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intra-venously, intra-muscularly), rectal, cutaneous, nasal, vaginal, by inhalation, route in the skin ( patch), or ocular. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, wetting devices, osmotic delivery, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions can be formulated in accordance with conventional pharmaceutical practices (see, e.g., Remington: The Science and Practice of Pharmacy, 2Orna, edition, 2000, ed. A. R. Gennaro, Lippincott Williams &; Wilkins, Philadelphia, United States, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, United States). Each compound of the combination can be formulated in a variety of ways that are known in the art. For example, the first and second agents can be formulated together or separately. Desirably, the first and second agents are formulated together for the simultaneous or almost simultaneous administration of the agents. Such co-formulated compositions may include the SSRI and the spheroid formulated together in the same pill, capsule, liquid, etc. It should be understood that, when referring to the formulation of "SSR1 / steroid combinations", the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations of the invention (e.g. , a combination of SSRI / glucocorticoid receptor modulator). By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be matched appropriately. Agents formulated individually or separately can be packaged together as a kit. Non-limiting examples include kits containing, e.g., two pills, a pill and a powder, a suppository and a liquid in a bottle, two topical creams, etc. The kit may include optional components that aid in the administration of the unit dose to patients, such as bottles to reconstitute powder forms, syringes for injection, special IV delivery systems, inhalers, etc. Additionally, the unit dose may contain instructions for the preparation and administration of the compositions. The kit can be manufactured as a single-use unit dose for a patient, multiple uses for a particular patient (at a constant dose or in which individual compounds can vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging"). The kit components can be assembled into cartons, ampoule packs, tubes, and the like. Controlled Release Formulations The administration of an SSRI / steroid combination of the invention in which both of the active agents are formulated for controlled release is useful where the SSRI or the steroid has, (i) a narrow therapeutic index (v. ., the difference between the concentration of plasma leading to harmful side effects or toxic reactions and the concentration of plasma leading to a therapeutic effect is small, generally, the therapeutic index, TI, is defined as the ratio of mean lethal dose ( LDS0) at average effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; (iii) a short biological half-life; or (iv) the drug-kinetic profile of each component must be modified to maximize the contribution of each agent, when used together, to an amount that is therapeutically effective for cytokine suppression. Accordingly, a sustained release formulation can be used to avoid frequent dosing that may be required to sustain the plasma levels of both agents at a therapeutic level. For example, in preferred oral pharmaceutical compositions of the invention, half-life and middle-residence times from 10 to 20 hours for one or both agents of the combination of the invention are observed. Many strategies may be sought to obtain controlled release in which the rate of release exceeds the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of parameters and formulation ingredients (eg, appropriate controlled release compositions and coatings). Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, micro-capsules, microspheres, nano-particles, patches, and liposomes. The release mechanism can be controlled such that the SSRI and / or steroid are released at intervals of periods, the release may be simultaneous, or a delayed release of one of the combination agents may be affected, when the early release of a particular agent it is preferred over the other. Controlled release formulations may include a degradable or non-degradable polymer, hydrogel, organogel, or other physical construction that modifies the bio-absorption, half-life or bio-degradation of the agent. The controlled release formulation can be a material that is painted or otherwise applied to the afflicted site, either internally or externally. In one example, the invention provides a bolus or biodegradable implant that is surgically inserted into or near a site of interest (e.g., near an artificial joint). In another example, the controlled release formulation implant can be inserted into an organ, such as in the lower intestine for the treatment of inflammatory bowel disease. The hydrogels can be used in controlled release formulations for the SSRI / steroid combinations of the present invention. Such polymers are formed from macromers with a polymerizable, non-degradable region, which is separated by at least one degradable region. For example, the water-soluble, non-degradable region can form the central core of the macromer and have at least two degradable regions that bind to the core, such that upon degradation, the non-degradable regions (in particular a polymerized gel) will separate, as described in US Pat. No. 5,626,863. Hydrogels can include acrylates, which can be readily polymerized by various starting systems such as eosin, ultraviolet or visible light. Hydrogels can also include polyethylene glycols (PEGs), which are highly hydrophilic and biocompatible. Hydrogels may also include oligoglycoleic acid, which is a poly (cx-hydroxy acid) that can be easily degraded by hydrolysis of the ester linkage to glycolic acid, a non-toxic metabolite. Other chain extensions may include polylactic acid, polycaprolactone, polyorthoesters, polyanhydrides or polypeptides. The entire network can be gelped into a biodegradable network that can be used to trap and homogeneously disperse SSRI / steroid combinations of the invention for delivery at a controlled rate. Chitosan and mixtures of chitosan with sodium carboxymethylcellulose (CMC-Na) have been used as vehicles for the sustained release of drugs, as described by Inouye et al., Drug Design and Delivery 1: 297-305, 1987. Mixtures of these compounds? agents of the combinations of the SSR1 / steroid invention, when compressed under 200 kg / cm2, form a tablet from which the active agent is slowly released upon administration to a subject. The release profile can be changed by varying the rates of chitosan, CMC-Na, and active agent (s). The tablets may also contain other additives, including lactose, CaHP04 dihydrate, sucrose, crystalline cellulose, or croscarmellose sodium. Several examples are given in Table 4. Table 4 Báichwal, in US Pat. No. 6,245,356, discloses a sustained release oral solid dosage form including agglomerated particles of a therapeutically active medicament (eg, a combination of SSR1 / steroid or its component of the present invention) in amorphous form, gel forming agent, an ionizable gel strength improving agent and an inert diluent. The gel-forming agent can be a mixture of xanthan gum and locust bean gum capable of cross-linking with xanthan gum when the gums are exposed to an ambient fluid. Preferably, the ionizable gel enhancing agent acts to improve the crosslinking strength between the xanthan gum and the locust bean gum and thereby prolong the release of the medicament component of the formulation. In addition to xanthan gum and locust bean gum, acceptable gel-forming agents that can also be used include those gel-forming agents well known in the art. Examples include naturally occurring or modified natural occurrence gums such as alginates, carrageenan, pectin, guar gum, modified starch, hydroxypropylmethylcellulose, methylcellulose, and other cellulosic or polymeric materials, such as, for example, sodium carboxymethylcellulose and hydroxypropylcellulose, and mixtures thereof. the previous ones. In another formulation useful for the combinations of the invention, Baichwal and Staniforth in US Pat. No. 5,135,757 describe a free flowing slow release granulation for use as a pharmaceutical excipient which includes from about 20 to about 70 percent or more by weight of a hydrophilic material that includes a heteropolysaccharide (such as, for example, xanthan gum or a derivative thereof) and a polysaccharide material capable of crosslinking the heteropolysaccharide (such as, for example, galactomannans, and most preferably, locust bean gum) in the presence of aqueous solutions, and from about 30 to about 80 percent by weight of an inert pharmaceutical filler (such as, for example, lactose, dextrose, sucrose, sorbitol, xylitol, fructose or their mixtures). After mixing the excipient with a combination of SSR1 / steroid, or combination agent, of the invention, the mixture is compressed directly into solid dosage forms such as tablets. The tablets thus formed slowly release the drug when ingested and exposed to gastric fluids. By varying the amount of excipient relative to the medicament, a slow release profile can be achieved. In another formulation useful for combinations of the invention, Shell, in US Pat. No. 5,007,790, discloses sustained-release oral drug dosage forms that release a medicament in solution at a rate controlled by the solubility of the medicament. The dosage form comprises a tablet or capsule that includes a plurality of particles of a drug dispersion of limited solubility (such as, for example, prednisolone, paroxetine, or any other agent of the SSR1 / steroid combination of the present invention. ) in a hydrophilic polymer, which swells with water, crosslinked, which maintains its physical integrity over the time of life of dosage but which subsequently dissolves rapidly. Once ingested, the particles swell to promote gastric retention and allow the gastric fluid to penetrate the particles, dissolve the drug and leach it from the particles, ensuring that the drug reaches the stomach in the state of solution that is less harmful to the stomach. stomach than solid-state medication. The eventual programmed dissolution of the polymer depends on the nature of the polymer and the degree of crosslinking. The polymer is non-fibrillating and substantially soluble in water in its non-crosslinked state, and the degree of crosslinking is sufficient to allow the polymer to remain insoluble for the desired period of time, typically at least about 4 to 8 hours up to 12 hours, with the option depending on the medication incorporated and the medical treatment involved. Examples of suitable cross-linked polymers that can be used in the invention are gelatin, albumin, sodium alginate, carboxymethyl cellulose, polyvinyl alcohol, and chitin. Depending on the polymer, crosslinking can be achieved by heat or radiation treatment or through the use of crosslinking agents such as aldehydes, poly (amino acids), metal ions and the like. Silicone microspheres for delivery of pH-controlled gastro-intestinal medicaments that are useful in the formulation of SSRl / steroid combinations of the invention have been described by Carelli et al., Int. J. Pharma-ceutics 179: 73-83 , 1999. The microspheres thus described are inter-penetrating, pH-sensitive polymer hydrogels, made by variable proportions of poly (methacrylic acid-co-methyl-tacrylate) (Eudragit L 100 or Eudragil S100) and cross-linked polyethylene glycol 8000 which are encapsulated in silicone microspheres in the size range of 500 to 1,000 μp ?. Slow release formulations may include a coating that is not readily soluble in water but that is slowly attacked and removed by water, or through which water may slowly permeate. Thus, for example, the SSRl / steroid combinations of the invention can be spray coated with a solution of a binder under continuously fluidizing conditions, such as are described by Kitamori et al., US Patent 4,036,948. Examples of water soluble binders include pre-gelatinized starch (e.g., pre-gelatinized corn starch, pre-gelatinized white potato starch, pre-gelatinized modified starch, water soluble celluloses (e.g., hydroxypropyl), cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose), polyvinyl pyrrolidone, polyvinyl alcohol, dextrin, gum arabic and gelatin, binders soluble in organic solvent, such as cellulose derivatives (e.g., phthalate of cellulose acetate, hydroxypropylmethyl cellulose phthalate, ethylcellulose) Combinations of the invention, or one of its components, with sustained release properties can also be formulated by spray drying techniques In one example, as described by Espositio and collaborators, Pharm. Dev. Technol. : 267-78, 2000, prednisolone was encapsulated in methylacrylate micro-particles (Eudragit RS) using a Mini Spray Dryer, model 190 (Buchi, Laboratorium Technik AG, Flawil, Gny). Optimal conditions for the formation of micro-particles were found at a feed rate (pump) of 0.5 mL / min of a solution containing 50 mg of prednisolone in 10 mL of acetonitrile, a nebulised air flow rate of 600 L / hr, hot air temperature heating at 80 ° C, and a suction drying air flow rate of 28 m3 / hr. Yet another sustained release form of SSR1 / steroid combinations can be prepared by micro-encapsulating the combination agent particles in membranes that act as micro-dialysis cells. In such a formulation, gastric fluid pates the walls of the microcapsule and swells the microcapsule, allowing the active agent to be dialyzed (see, for example, Tsuei et al., US Patent 5,589,194). A commercially available sustained release system of this type consists of microcapsules having acacia gum / gelatin / ethyl alcohol membranes. This product is available from Eurand Limited (France) under the name Diffucaps. Micro-capsules formulated in this way can be carried in a conventional gelatin capsule or made into tablets. Formulations of extended and / or controlled release of both SSRIs and corticosteroids are known. For example, Paxil CR, commercially available from GlaxoSmithKline, is a form of extended release of paroxetine hxdrochloride in a degradable polymer matrix (GEOMATRIX, see also US Patents 4,839,177, 5,102,666, and 5,422,123), which also has an enteric coating for delay the onset of drug release until after the tablets have passed through the stomach. For example, US Pat. No. 5,102,666 describes a polymer controlled release composition comprising a reaction complex formed by the interaction of (1) a calcium polycarbophil component which is a fibrous crosslinked carboxy functional polymer, which swells in water, but insoluble in water, the polymer containing (a) a plurality of repeating units of which at least 80% contain at least one carboxyl functionality, and (b) about 0.05 to about 1.5% crosslinking agent substantially free of polyalkenyl polyether, the percentages being based on the weights of the unpolymerized repeat unit and crosslinking agent, respectively, with (2) water, in the presence of an active agent selected from the group consisting of SSRIs such as paroxetxa. The amount of calcium polycarbophil present is from about 0.1 to about 99% by weight, for example about 10%. The amount of active agent present is from about 0.0001 to about 65% by weight, for example between about 5 and 20%. The amount of water present is from about 5 to about 200% by weight, for example between about 5 and 10%. The interaction is carried out at a pH of between about 3 and about 10, for example about 6 to 7. The calcium polycarbophil is originally present in the form of a calcium salt containing from about 5 to around 25% calcium. Other examples of extended release formulations are described in US Pat. No. 5,422,123. Thus, a system for the controlled release of an active substance which is an SSRI such as paroxetine, comprising (a) a deposit core comprising an effective amount of the active substance and having a defined geometric shape, and (b) a support platform applied to the reservoir core, wherein the reservoir core contains at least the active substance, and at least one member selected from the group consisting of (1) a polymeric material that swells in contact with water or aqueous liquids and a material Gelatable polymer where the ratio of polymeric material that swells to gelable polymeric material is in the range of 1: 9 to 9: 1, and (2) a simple polymeric material having both swelling and gel forming properties, and wherein the support platform is an elastic support, applied to said reservoir core such that it partially covers the surface of the reservoir core and follows changes due to the idratation of the deposit core and be soluble slowly and / or slowly form gel in aqueous fluids. The support platform may comprise polymers such as hydroxypropylmethylcellulose. plasticizers such as a glyceride, binders such as polyvinyl pyrrolidone, hydrophilic agents such as lactose and silica, and / or hydrophobic agents such as magnesium stearate and glycerides. The polymer (s) typically account for 30 to 90% by weight of the support platform, for example about 35 to 40%. The plasticizer can account for at least 2% by weight of the support platform, for example about 15 to 20%. Binder (s), hydrophilic agent (s) and hydrophobic agent (s) typically amount up to about 50% by weight of the support platform, for example about 40 to 50%. In another example, an extended release formulation for venlafaxine (Effexor XR) is available commercially from Wyeth Pharmaceuticals. This formulation includes venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose, coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose (see US 6,403,120 and 6,419,958). A controlled release formulation of budesoni-da (3 mg capsules) for the treatment of inflammatory bowel disease is available from AstraZeneca (marketed as Entocort). A sustained release formulation useful for corticosteroids is also described in US patent 5,792,476, where the formulation includes 2.5-7 mg of a glucocorticoid as active substance with a sustained sustained release such that at least 90% by weight of the glycogen -corticoid is released for a period of about 40-80 min, starting in about 1-3 hr after entry of said glucocorticoid into the patient's small intestine. To make these low dose levels of active substance possible, the active substance, i.e., the glucocorticoid, such as prednisolone or prednisone, is micronized, further mixed with known diluents, such as starch and lactose, and granulated with PVP (polyvinyl pyrrolidone). In addition, the granulate is laminated with an inner layer of sustained release resistant to a pH of 6.8 and an outer layer of sustained release resistant to a pH of 1.0. The inner layer is made of Eudragit RL (acrylic and methacrylic ester copolymer with a low content of quaternary ammonium groups) and the outer layer is made of Eudragil L (anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester) . A two-layer tablet can be formulated for a SSR1 / steroid combination of the invention in which different custom granulations are made for each combination agent and the two agents are compressed in a two-layer press to form a tablet simple. For example, 12.5, 25, 37.5, or 50 mg of paroxetine, formulated for a controlled release that results in a t1 / 2 of paroxetine for 15 to 20 hours can be combined in the same tablet with 3 mg of prednisolone, which is formulates such that t1 / 2 approaches that of paroxetine. Examples of paroxetine extended release formulations, including those used in two-layer tablets, can be found in US Pat. No. 6,548,084. In addition to controlling the release rate of prednisolone in vivo, an enteric or delayed-release layer can be included which delays the release of the drug such that the Tmax of prednisolone approaches that of paroxetine (i.e., 5 to 10). hours) . Cyclodextrins are cyclic polysaccharides containing D (+) - glucopyranose units of natural occurrence in an α- (1,4) bond. Alpha-, beta-, and gamma-cyclodextrins, which contain, respectively, six, seven or eight glucopyranose units, are the most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98 / 55148. Structurally, the cyclic nature of a cyclodextrin forms a bull or donut shape having a hydrophobic or internal apolar cavity, the secondary hydroxyl groups located on one side of the cyclodextrin bull and the primary hydroxyl groups located on the other. The side on which the secondary hydroxyl groups are located has a wider diameter than the side on which the primary hydroxyl groups are located. The hydrophobic nature of the inner cyclodextrin cavity allows the inclusion of a variety of compounds. (Comprenhensive Supramolecular Chemistry, volume 3, J. L. Atwood et al., Editors, Pergamon Press (1996); Cserhati, Analytical Biochemistry 225: 328-32, 1995; Husain et al., Applied Spectroscopy 46: 652-8, 1992). Cyclodextrins have been used as a delivery vehicle for several therapeutic compounds by forming inclusion complexes with various drugs that can fit within the hydrophobic cavity of the cyclodextrin or by forming non-covalent association complexes with other biologically active molecules. . US Patent 4,727,064 discloses pharmaceutical preparations consisting of a medicament with substantially low water solubility and a water-soluble, amorphous cyclodextrin-based mixture, in which the medicament forms an inclusion complex with the cyclodextrins of the mixture. The formation of a cyclodextrin complex can modify the solubility properties of the drug, dissolution rate, bioavailability, and / or stability. For example, cyclodextrins have been described to improve bioavailability of prednisolone, as described by Uekama et al., J. Pharm Dyn. 6: 124-7, 1983. A complex of β-cyclodextrin / prednisolone can be prepared by adding both components in water and stirring at 25 ° for 7 days. The resulting precipitate recovered is a 1: 2 prednisolone / cyclodextrin complex. Sulfobutyl ether-3-cyclodextrin (SBE-P-CD, commercially available from CyDex, Inc., Overland Park, Kansas, United States, and marketed as CAPTISOL) may also be used as an adjunct in the preparation of sustained release formulations of antiviral agents. the combinations of the present invention. For example, a sustained release tablet has been prepared which includes prednisolone and SBE-CD compressed in a hydroxypropyl methylcellulose matrix (see Rao et al., J. Pharm, Sci. 90: 807-16, 2001). In another example of the use of several cyclodextrins, EP 1109806 Bl discloses paroxetine cyclodextrin complexes, wherein OÍ-, β- or β-cyclodextrins [including eptakis (2,6-di-0-methyl) - β-cyclodextrin, (2) , 3, 6-tri-O-methyl) -β-cyclodextrin, monosuccinyl eptakis (2,6-di-O-methyl) -β-cyclodextrin, or 2-hydroxypropyl-β-cyclodextrin] in anhydrous or hydrated form formed relationships complexes of agent to cyclodextrin from 1: 0.25 to 1:20, can be obtained. Polymeric cyclodextrins have also been prepared, as described in patent applications US 10 / 021,294 and 10 / 021,312. The cyclodextrin polymers thus formed may be useful for formulating agents of the combinations of the present invention. These polyfunctional polymeric cyclodextrins are commercially available from Insert Therapeutics, Inc., Pasadena, California, United States. As an alternative to direct complex formation with agents, cyclodextrins can be used as an auxiliary additive, e.g., as a carrier, diluent or solubilizer. Formulations including cyclodextrins and other agents of the combinations of the present invention (ie, SSRIs and / or steroids) can be prepared by methods similar to the preparations of the cyclodextrin formulations described herein. Liposomal Formulations One or both components of the SSR1 / steroid combinations of the invention, or mixtures of the two components together, can be incorporated into liposomal vehicles for administration. Liposomal vehicles are components of three general types of vesicle-forming lipid components. The first includes vesicle-forming lipids that will form the bulk of the vesicle structure in the liposome. Generally, these vesicle-forming lipids include any amphipathic lipid having hydrophobic and polar head group moieties, and which (a) can spontaneously form in two-layered vesicles in water, as used by phospholipids, or (b) are incorporated Stably in two layers of lipids, with its hydrophobic fraction in contact with the interior, the hydrophobic region of the two-layer membrane, and its polar head group fraction oriented toward the outer, polar surface of the membrane. Vesicle-forming lipids of this type are preferably ones having two hydrocarbon chains, typically acyl chains, and a polar head group. Included in this class are phospholipids, such as phosphatidylcholine (PC), PE, phosphatidic acid (??), phosphatidylinositol (PI), and sphingomyelin (SM), where the two hydrocarbon chains are typically between about 14-22. carbon atoms in length, and have various degrees of unsaturation. The above-described lipids and phospholipids whose acyl chains have a variety of degrees of saturation can be obtained commercially, or prepared according to published methods. Other lipids that may be included in the invention are glycolides and sterols, such as cholesterol. The second general component includes a vesicle-forming lipid that is derived with a polymer chain that will form the polymer layer in the composition. Vesicle-forming lipids are any of those described for the first general vesicle-forming lipid component. Vesicle-forming lipids with diacyl chains, such as phospholipids, are preferred. An exemplary phospholipid is phosphatidy-ethanolamine (PE), which provides a reactive amino group which is convenient for coupling to activated polymers. An exemplary PE is distearil PE (DSPE). The preferred polymer in the derivatized lipid is polyethylene glycol (PEG), preferably a PEG chain having a molecular weight between 1,000-15,000 Daltons, more preferably between 2,000 and 10,000 Daltons, most preferably between 2,000 and 5,000 Daltons. Other hydrophilic polymers that may be suitable include polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide and polydimethylacrylamide, polylactic acid, polyglycolic acid, and derived celluloses, such as hydroxymethylcellulose and hydroxyethylcellulose. Additionally, block copolymers or random compollomers of these polymers, particularly PEG segments, may be suitable. Methods for preparing derivatized lipids with hydrophilic polymers, such as PEG, are well known, e.g. , as described in US Patent 5,013,556. A third general component of vesicle-forming lipid, which is optional, is an anchor lipid by which a target fraction is anchored to the liposome, through a polymer chain at the anchor. Additionally, the target group is placed at the far end of the polymer chain in such a way that the biological activity of the target group is not lost. The lipid anchor has a hydrophobic fraction that serves to anchor the lipid in the outer chain of the two-layer surface of the liposome, a polar head group to which the inner end of the polymer covalently attaches, and a free polymer end (outer) that is or may be activated for covalent coupling to the target fraction. Methods for preparing lipid anchor molecules of this type are described below. The lipid components used in forming the liposomes are preferably present in a molar ratio of about 70-90 percent of vesicle-forming lipids, 1-25 percent of lipid-derived polymer, and 0.1-5 percent of anchor lipid. An exemplary formulation includes 50-70 molar percent non-derivatized PE, 20-40 percent cholesterol, 0.1-1 molar percent PE-PEG polymer (3,500) with a chemically reactive group at its free end for coupling to a fraction of target, 5-10 mole percent PE derived with PEG 3,500 polymer chains, and 1 molar percent alpha-tocopherol. Liposomes are preferably prepared to have substantially homogeneous sizes in a selected size range, typically between about 0.03 to 0.5 microns. An effective sizing method for REVs and MLVs involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a uniform pore size selected in the range of 0.03 to 0.2 microns, typically 0.05, 0.08, 0.1 or 0.2. mieras The pore size of the membrane corresponds more or less to the larger sizes of liposomes produced by extrusion through that membrane, particularly where the preparation is extruded two or more times through the same membrane. Homogenization methods are also useful for reducing liposomes to sizes of 100 nm or less. The liposomal formulations of the present invention include at least one surface active agent. Active surface active agents useful for the formulation of the SSRI / steroid combinations described herein include compounds belonging to the following classes: polyethoxy-fatty acids, PEG-fatty acid diesters, mono-ester mixtures and di-ester PEG-fatty acid, polyethylene glycol-glycerol-fatty acid esters, alcohol-fat transesterification products, polyglycerized fatty acids, propylene glycol-fatty acid esters, mixtures of propylene glycol esters and glycerol, mono- and di-esters -glycerides, sterol and sterol derivatives, polyethylene glycol-sorbit n-fatty acid esters, polyethylene glycol-algayl ethers, sugar esters, polyethylene glycol-alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan esters- fatty acid, lower alcohol-fatty acid esters, and ionic surfactants. Commercially available examples for each kind of excipient are provided below. The polyethoxylated fatty acids can be used as excipients for the formulation of SSR1 / steroid combinations described herein. Examples of commercially available polyethylene glycol monoester fatty acid surfactants include: PEG monolaurate 4-100 (Crodet L series, Croda), PEG 4-100 monolaurate (Crodet 0 series, Croda), PEG monostearate 4-100 (Crodet series S, Croda, and Myrj Series, Atlas / lCI), distearate of PEG 400 (Cithrol 4DS series, Croda), PEG 100, 200 or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200 or 300 monooleate ( Cithrol MO series, Croda), PEG 400 dioleate (Cithrol series 4D0, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS-1EX, Nikko, and Coster Kl, Condea), PEG-2 stearate (Nikkol MYS-2, Nikko), PEG-2 oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg 200 ML, PPG), PEG-4 oleate (Mapeg 200 MO, PPG), stearate of PEG-4 (Kessco PEG 200 MS, Stepan), PEG-5 stearate (Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), PEG-6 oleate (Algon OL 60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschen SpA), PEG-6 laurate (Kessco PEG300 ML, Stepan), laurate of PEG-7 (Lauridac 7, Condea), stearate of PEG-6 (Kessco PEG300 MS, Stepan), laurate of PEG-8 (Mapeg 400 ML, PPG), oleate of PEG-8 (Mapeg 400 MO, PPG) , PEG-8 stearate (Mapeg 400 MS, PPG), PEG-9 oleate (Emulsifier A9, Condea), stearate of PEG-9 (Cremophor S9, BASF), laurate of PEG-10 (Nikkol MYL-10, Nikko), oleate of PEG-10 (Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10, Nikko), PEG-12 laurate (KESSCO PEG 600 ML, Stepan), PEG-12 oleate (Kessco PEG 600 MO, Stepan) , PEG-12 ricinoleate (CAS # 9004-97-1), PEG-12 stearate (Mapeg 600 MS, PPG), PEG-15 stearate (Nikkol TMGS-15, Nikko), PEG-15 oleate (Nikkol TMGO-15, Nikko), PEG-20 laurate (Kessco PEG 1000 ML, Stepan), PEG-20 oleate (Kessco PEG 100 MO, Stepan), PEG-20 stearate (Mapeg 1000 MS, PPG), stearate PEG-25 (Nikkol MYS-25, Nikko), PEG-32 laurate (Kessco PEG 1540 ML, Stepan), PEG-32 oleate (Kessco PEG 1540 MO, Stepan), stearate of PEG-32 (Kessco PEG 1540 MS, Stepan), stearate of PEG-30 (Myrj 51), laurate of PEG-40 (Crodet L40, Croda), oleate of PEG-40 (Crodet O40, Croda), stearate of PEG-40 (Emerest 2715, Henkel), stearate of PEG-45 (Nikkol MYS-45, Nikko), stearate of PEG-50 (Myrj 53), stearate of PEG-55 (Nikkol MYS-55, Nikko), oleate from PEG-100 (Crodet 0-100, Croda), stearate from PEG-100 (Ariacel 165, ICI), oleate from PEG-200 (Albunol 200 MO, Taiwan Surf.), Oleate from PEG-400 (LACTOMUL, Henkel), and PEG-600 oleate (Albumol 600 MO, Taiwan Surf.). Formulations of one or both components of the SSR1 / steroid combinations according to the invention may include one or more of the above polyethoxylated fatty acids. Polyethylene glycol fatty diesters can also be used as excipients for the SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol-fatty acid diesters include: PEG-4 dilaurate (Mapeg 200 DL, PPG), PEG-4 dioleate (Mapeg 200 OD, PPG), PEG-4 distearate (Kessco 200 DS, Stepan ), PEG-6 dilaurate (Kessco PEG 300 DL, Stepan), PEG-6 dioleate (Kessco PEG 30 OD, Stepan), PEG-6 distearate (Kessco PEG 300 DS, Stepan), PEG-8 dilaurate ( Mapeg 400 DL, PPG), PEG-8 dioleate (Mapeg 400 DO, PPG), PEG-8 distearate (Mapeg 400 DS, PPG), PEG-10 dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (Kessco PEG 600 DL, Stepan), PEG-12 distearate (Kessco PEG 600 DS, Stepan), PEG-12 dioleate (Mapeg 600 OD, PPG), PEG-20 dilaurate (Kessco PEG 1000 DL, Stepan), dioleate PEG-20 (Kessco PEG 1000 DO, Stepan), distearate of PEG-20 (Kessco PEG 1000 DS, Stepan), dilaurate of PEG-32 (Kessco PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco PEG 1540 OD , Stepan), PEG-32 distearate (Kessco PEG 1540 DS, Stepan), PEG-40 dioleate 0 (Cithrol series 4D0, Croda), and distearate of PEG-400 (Cithrol series 4DS, Croda). Formulations of the SSRI / steroid combinations according to the invention may include one or more of the above polyethylene glycol-fatty acid diesters. Mono- and di-ester mixtures of PEG-fatty acid can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of commercially available PEG-fatty acid mono- and di-ester mixtures include: mono, PEG-4-150 dilaurate (Kessco PEG 200-6000 mono, Dilaurate, Stepan), mono, PEG-4-150 dioleate (Kessco PEG 200-6000 mono, Dioleate, Stepan), and mono, distearate of PEG-4-150 (Kessco 200-6000 mono, Distearate, Stepan). Formulations of the SSRI / steroid combinations according to the invention may include one or more of the above PEG-fatty acid mono- and di-ester mixtures. further, polyethylene glycol glycerol fatty acid esters can be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of polyethylene glycol glycerol fatty acid esters include: glyceryl laurate from PEG-20 (Tagat L, Goldschmidt), glyceryl laurate from PEG-30 (Tagat L2, Goldschmidt), glyceryl laurate from PEG-15 (Glycerox L series, Croda), glyceryl laurate from PEG-40 (Glycerox L series, Croda), glyceryl stearate from PEG-20 (Capmul EMG, ABITEC, and Aldo MS-20 KFG, Lonza), glyceryl oleate from PEG-20 (Tagat O, Goldschmid ), and PEG-30 glyceryl oleate (Tagat 02, Goldschmidt). Formulations of the SSRI / steroid combinations according to the invention may include one or more of the above polyethylene glycol glycerol fatty acid esters. The alcohol-oil transesterification products can also be used as excipients for the formulation of the SSRI / steroid combinations described herein. Examples of alcohol-oil transesterification products include: castor oil from PEG-3 (Nikkol CO-3, Nikko), castor oil from PEG-5, 9, and 16 (ACCONON CA series, ABITEC), castor oil of PEG-20 (Emalex C-20, Nihon Emulsion), castor oil of PEG-23 (Emulsifier EL23), castor oil of PEG-30 (Incrocas 30, Croda), castor oil of PEG-35 (Incrocas- 35, Croda), castor oil from PEG-38 (Emulsifier EL 65, Condea), castor oil from PEG-40 (Emalex C-40, Nihon Emulsion), castor oil from PEG-50 (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin PRT 56, Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG-castor oil 200 (Eumulgin PRT 200, Pulcra SA), hydrogenated PEG-5 castor oil (Nikkol HCO-5, Nikko), hydrogenated PEG-7 castor oil (Cremophor W07, BASF), hydrogenated PEG-10 castor oil (Nikkol HCO-10, Nikko), hydrogenated PEG-20 castor oil (Nikkol HCO-20, Nikko), hydrogenated PEG-25 castor oil (Simulsol 1292, Seppic), hydrogenated PEG-30 castor oil (Nikkol HCO-30, Nikko), hydrogenated PEG-40 castor oil (Cremophor H 40, BASF), hydrogenated PEG-45 castor oil (Cerex ELS 450, Auschem Spa), hydrogenated PEG-50 castor oil (Emalex HC-50, Nihon Emulsion), hydrogenated PEG-60 castor oil (Nikkol HCO-60, Nikko), hydrogenated PEG-80 castor oil (Nikkol HCO-80, Nikko), hydrogenated PEG-100 castor oil (Nikkol HCO-100, Nikko), PEG-6 corn oil (Labrafil M 2125 CS, Gattefosse), almond oil from PEG-6 (Labrafil M 1966 CS, Gattefosse), apricot seed oil from PEG-6 (Labrafil M 1944 CS, Gattefosse), olive oil from PEG-6 (Labrafil M 1980 CS, Gattefosse), PEG-6 peanut oil (Labrafil 1969 CS, Gattefosse), hydrogenated PEG-6 palm seed oil (Labrafil M 2130 BS, Gattefosse), PEG-6 palm seed oil (Labrafil M 2130 CS, Gattefosse), thiolein from PEG-6 (Labrafil M 2735 CS, Gattefosse), corn oil from PEG-8 (Labrafil WL 2609 BS, Gattefosse), corn glycerides from PEG-20 (Crovol M40, Croda), almond glycerides of PEG-20 (Crovol A40, Croda), thioleate of PEG-25 (TAGAT TO, Goldschmidt), palm seed oil of PEG-40 (Crovol PK-70), corn glycerides of PEG-60 (Crovol M70, Croda), almond glycerides from PEG-60 (Crovol 70, Croda), capric / caprylic triglyceride from PEG-4 (Labrafac Hydro, Gattefosse), caprylic / capric glycerides from PEG-8 (Labrasol, Gattefosse), glycerides caprylic / capric of PEG-6 (SOFTIGEN 767, Huís), lauroyl glyceride macrogol-32 (GELUCIRE 44/14, Gattefosse), glyceride of stearoyl raacrogol (GELUCIRE 50/13, Gattefosse), mono, di, tri, tetra esters of vegetable oils and sorbitol (SorbitolGlyceride, Gattefosse), pentaerythrityl tetraisostearate (Crodamol PTIS, Croda), pentaerythritil distearate (Albunol DS, Taiwan Surf. ), pentaerythritil tetraoleate (Liponate PO-4), Lipo Chem.), Pentaerythritil tetrastearate (Liponate PS-4, Lipo Chem.), And pentaerythritol tetraoctanoate (Nikkol Pentarate 408, Nikko). Also included as oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K, etc. Thus, derivatives of these vitamins, such as tocopheryl succinate PEG-1000 (TPGS, available from Eastman), are also suitable surfactants. Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above alcohol-oil transesterification products. Polyglycerized fatty acids can also be used as excipients for the formulation of the SSR1 / steroid combinations described herein. Examples of commercially available polyglycerized fatty acids include: polyglyceryl-2 stearate (Nikkol DMGS, Nikko), polyglyceryl-2 oleate (Nikkol DMGO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), polyglyceryl-3 oleate (Caprol 3GO, ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn 1-0, Nikko), polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol 6-1-0, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Decaglyn 1-0, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S, Nikko), ricinoleate polyglyceryl-6 (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-0, Nikko), polyglyceryl-3 dioleate (Cremophor G032, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-0, Nikko), polyglycan dioleate ril-6 (Caprol 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl-10 trioleate (Nikkol Decaglyn 3-0, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-0, Nikko ), polyglyceryl-10-septaoleate (Nikkol Decaglyn 7-0, Nikko), polyglyceryl-10 tetraoleate (Caprol 10G40, ABITEC), polyglyceryl-10 decastisostearate (Nikkol Decaglyn 10-IS, Nikko), polyglyceryl-101 decaoleate (Drewopol 10-10-0, Stepan) , mono, polyglyceryl-10 dioleate (Caprol PGE 860, ABITEC), and polyglyceryl polyricinoleate (Polymus, Henkel). Formulations of the SSR1 / steroid combinations according to the invention can include one or more of the above polyglycerized fatty acids. In addition, propylene glycol-fatty acid esters can be used as excipients for the formulation of SSR1 / steroid combinations described herein. Examples of commercially available propylene-glycol-fatty acid esters include: propylene glycol monocaprylate (Capryol 90, Gattefosse), propylene glycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene myristate glycol (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), propylene glycol hydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel), propylene glycol isostearate, propylene glycol monooleate (Myverol P-06, Eastman) , propylene glycol dicaprylate (Captex 200, ABITEC), propylene glycol dioctanoate (Captex 800, ABITEC), propylene glycol caprylate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco PGDS, Stepan ), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikkol PDD, Nikko). Formulations of the SSRI / steroid combinations according to the invention may include one or more of the above propylene glycol fatty acid esters. Mixtures of propylene glycol esters and glycerol esters can also be used as excipients for the fomrulation of the SSRI / steroid combinations described herein. A preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants include: oleic (ATMOS 300, ARLACEL 186, ICI), and stearic (ATMOS 150). Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the mixtures of propylene glycol esters and glycerol esters above. Additionally, mono- and di-glycerides can be used as excipients for the formulation of the SSR1 / steroid combinations described herein. Examples of commercially available mono- and di-glycerides include: monopalmitolein (C16: 1) (Larodan), monoelaidine (C18: 1) (Larodan), monocaproine (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin (Larodan), glyceryl monomiristate (C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18: l) (PEGEOL, Gattefos-se) , glyceryl monooleate (Myverol, Eastman), monooleate-glycerol linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen 701, Huís), glyceryl monolaurate (ALDO MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul GMS, ABITEC), glyceryl mono- and di-oleate (Capmul GMO-K, ABITEC), palmitic / stearic glyceryl (CUTINAMD-A, ESTAGEL-G18), glyceryl acetate (Lamegin EE, Grunau GmbH), glyceryl laurate (Imwitor 312, Huís), glyceryl caprylate (Imwitor 308, Huís), glyceryl caprylate / caprate (Capmul MC, ABITEC), mono- and di-glycerides of caprylic acid (Imwitor 988, Huís), caprylic / capric glycerides (Imwitor 742, Huís), monoglycerides mono- and di-acetylated (Myvacet 9-45, Eastman), glyceryl monostearate (Aldo MS, Aracel 129, ICI), lactic acid esters of mono and diglycerides (LAMEGIN GLP, Henkel), dicaproine (C6) (Larodan), dicaprin ( CIO) (Larodan), dioctanoin (C8) (Larodan), dimiristin (C14) (Larodan), dipalmitin (C16) (Larodan), distetearin (Larodan), glyceryl dilaurate (C12) (Capmul GCL, ABITEC), glyceryl dioleate (Capmul GDO, ABITEC), glycerol esters of fatty acids (GELUCI E 39/01, Gattefos-se), dipalmitoleína (C16: l) (Larodan), 1,2- and 1,3 -diolone (C18: 1) (Larodan), dielaidine (C18: 1) (Larodan), and dilinolein (C18: 2) (Larodan). Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above mono- and di-glycerides. Sterol and sterol derivatives can also be used as excipients for the formulation of the SSR1 / steroid combinations described herein. Examples of sterol and sterol derivatives commercially available include: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol (Phytosterol GENEROL series, Henkel), PEG-25 phytosterol (Nikkol BPSH) -25, Nikko), PEG-5 soyaterol (Nikkol BPS-5, Nikko), PEG-10 soyaterol (Nikkol BPS-10, Nikko), PEG-20 soyaterol (Nikkol BPS-20, Nikko), and PEG-30 soyaterol (Nikkol BPS-30, Nikko). Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above sterols and sterol derivatives. Polyethylene glycol-sorbitan fatty acid esters may also be used as excipients for the formulation of the SS l / steroid combinations described herein. Examples of commercially available polyethylene glycol-sorbitan fatty acid esters include: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween 20, Atlas / lCl), PEG monolaurate -4 sorbitan (Tween 21, Atlas / lCI), PEG-80 sorbitan monolaurate (Hodag PSML-80, Calgene), PEG-6 sorbitan monolaurate (Nikkol GL-1, Nikko), PEG-20 sorbitan monopalmitate (Tween 40, Atlas / lCl), PEG-20 sorbitan monostearate (Tween 60, Atlas / lCl), PEG-4 sorbitan monostearate (Tween 61, Atlas / lCl), PEG-8 sorbitan monostearate (DACOL MSS, Condea ), PEG-6 sorbitan monostearate (Nikkol TS106, Nikko), PEG-20 sorbitan tristearate (Tween 65, Atlas / lCl), PEG-6 sorbitan tetrastearate (Nikkol GS-6, Nikko), PEG-60 tetrastearate sorbitan (Nikkol GS-460, Nikko), monooleate of PEG-5 sorbitan (Tween 81, Atlas / lCI), monooleate of PEG-6 sorbitan (Nikkol TO-106, Nikko), monooleate of PEG-20 sorbitan (Tween 80, Atla s / lCl), PEG-40 sorbitan oleate (Emalex ET 8040, Nihon Emulsion), PEG-20 sorbitan trioleate (Tween 85, Atlas / lCI), PEG-6 sorbitan tetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (Nikkol GO-430, Nikko), PEG-40 sorbitan tetraoleate (Nikkol GO-440, Nikko), PEG-20 sorbitan monoisostearate (Tween 120, Atlas / lCl), PEG sorbitol hexaoleate ( Atlas G-1086, ICI), polysorbate 80 (Tween 80, Pharma), polysorbate 85 (Tween 85, Pharma), polysorbate 20 (Tween 20, P arma), polysorbate 40 (Tween 40, Pharma), polysorbate 60 (Tween 60 , Pharma), and PEG-6 sorbitol hexatestearate (Nikkol GS-6, Nikko). Formulations of the SSRI / steroid combinations according to the invention may include one or more of the above polyethylene glycol-sorbitan fatty acid esters. In addition, glycol-alkyl polyethylene ethers can be used as excipients for the formulation of SSRI / steroid combinations described herein. Examples of commercially available polyethylene glycol-alkyl ethers include: PEG-2 oleyl ether, olet-2 (Brij 92/93, Atlas / lCl), PEG-3 oleyl ether, olet-3 (Volpo 3, Croda), PEG- 5 oleyl ether, olet-? (Volpo 5, Croda), PEG-10 oleyl ether, olet-10 (Volpo 10, Croda), PEG-20 oleyl ether, olet-20 (Volpo 20, Croda), PEG-4 lauryl ether, laureth-4 (Brij 30, Atlas / lCl), PEG-9 lauryl ether, PEG-23 lauryl ether, lauret-23 (Brij 35, Atlas / lCl), PEG-2 cetyl ether (Brij 52, ICI), PEG-10 cetyl ether (Brij 56, ICI), PEG-20 cetyl ether (Brij 58, ICI), PEG-2 stearyl ether (Brij 72, ICI), PEG-10 stearyl ether (Brij 76, ICI), PEG- 20 stearyl ether (Brij 78, ICI), and PEG-100 stearyl ether (Brij 700, ICI). Formulations of the SSRI / steroid combinations according to the invention may include one or more of the above polyethylene glycol-alkyl ethers. Sugar esters can also be used as excipients for the formulation of SSRI / steroid combinations described herein. Examples of commercially available sugar esters include: sucrose distearate (SUCRO ESTER 7, Gattefosse), distearate / sucrose monostearate (SUCRO ESTER 11, Gattefosse), sucrose dipalmitate, sucrose monostearate (Crodesta F-160, Croda), monopalmitate of sucrose (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubishi- Kasei). Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above sugar esters. Polyethylene glycol-alkyl phenols can also be used as excipients for the formulation of combinations of SSR1 / steroid described herein. Examples of commercially available polyethylene glycol-alkyl phenols include: PEG-10-100 series nonylphenol (Triton X series, Rohm &Haas) and PEG-15-100 octylphenol ether series (Triton N series, Rohm &Haas). Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above polyethylene glycol-alkyl phenols. Copolymers of polyoxyethylene-polyoxypropylene blocks can also be used as excipients for the formulation of SSR1 / steroid combinations described herein.

These surfactants are available under various trade names, including one or more of Synperonic PE series (ICI), Pluronic series (BASF), Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these copolymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula (X): HO (C2H40) a (C3H60) b (C2H40) aH (X) where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively. These copolymers are available in molecular weights ranging from 1,000 to 1,500 Daltons, and with ratios of ethylene oxide to propylene oxide between 0.1 and 0.8 by weight. Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above polyoxyethylene-polyoxypropylene block copolymers. Polyoxyethylenes, such as PEG 300, PEG 400, and PEG 600, can be used as excipients for the formulation of the SSR1 / steroid combinations described herein. Fatty acid sorbitan esters can also be used as excipients for the formulation of the SSR1 / steroid combinations described herein. Examples of commercially available fatty acid sorbitan esters include: sorbitan monolaurate (Span-20, Atlas / lCl), sorbitan monopalmitate (Span-40, Atlas / lCl), sorbitan monooleate (Span-80, Atlas / lCl) , sorbitan monostearate (Span-60, Atlas / lCI), sorbitan trioleate (Span-85, Atlas / lCI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas / ICI) , sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquistearate (Nikko SS-15, Nikko). Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above fatty acid-sorbitan esters. Lower alcohol esters (C2 to Cj and fatty acids (C8 to C18) are suitable surfactants for use in the invention Examples of these surfactants include: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda) , isopropyl pamitate (Crodamol IPP, Croda), ethyl linoleate (Nikkol VF-E, Nikko), and isopropyl linoleate (Nikkol VF-IP, Nikko) Formulations of the SSR1 / steroid combinations according to the invention can include one or more of the above lower fatty acid esters., ionic surfactants can be used as excipients for the formulation of the SSR1 / steroid combinations described herein. Examples of useful ionic surfactants include: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, linoleate sodium, sodium linolenate, sodium stearate, sodium lauryl sulfate (dodecyl), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium urosdeoxycholate, sodium chenodeoxycholate, sodium taurokenedeoxycholate, sodium glyco-deoxychoxycholate, sodium colisarcosinate, sodium N-methyl taurocholate, egg yolk phosphatide, hydrogenated soy lecithin, dimiristoil lecithin, lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid, phosphatidyl g licerol, phosphatidyl serine, diethanolamine, phospholipids, polyoxyethylene-10-oleyl ether phosphate, esterification products of fatty alcohols or fatty alcohol ethoxylates, with acid or phosphoric anhydride, ether carboxylates (by oxidation of terminal OH group of alcohol ethoxylates) fatty), succinylated monoglycerides, sodium stearyl fumarate, hydrogenated stearoyl propylene glycol succinate, mono / diacetylated tartaric acid esters of mono- and di-glycerides, citric acid esters of mono-, diglycerides, glyceryl-lacto-esters of acids fatty acids, acyl lactylates, fatty acid lactylic esters, sodium stearoyl-2-lactylate, sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ethoxylated alkyl sulphates, alkyl benzene sulfones, O-olefin sulfonates, isethionates of acyl, acryl taurates, alkyl glyceryl ether sulphonates, octyl sulfosuccinate deodium, undecylenamido-MEA-sodium sulfosuccinate , hexadecyl triammonium bromide, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (trialkylglycine), lauryl betaine (N- lauryl-N, N-dimethylglycine), and ethoxylated amines (polyoxyethylene-15 coco amine). For simplicity, typical counter-ions are not provided above. It will be appreciated by one skilled in the art, however, that any bio-acceptable counter ion can be used. For example, although the fatty acids are shown as sodium salts, other cation counter ions may also be used, such as, for example, alkali metal or ammonium cations. Formulations of the SSR1 / steroid combinations according to the invention may include one or more of the above ionic surfactants. The excipients present in the formulations of the invention are present in amounts such that the carrier forms a clear, or opalescent, aqueous dispersion of the SSRI, the spheroid, or the combination of SSR1 / steroid sequestered within the liposome. The relative amount of a surface active excipient necessary for the preparation of liposomal nanoparticle or solid lipid formulations is determined using known methodology. For example, liposomes can be prepared by a variety of techniques, such as those detailed in Szoka et al., 1980. Multi-lamellar vesicles (MLVs) can be formed by simple lipid film hydration techniques. In this process, a mixture of liposome-forming lipids of the detailed type previously dissolved in a suitable organic solvent is evaporated in a vessel to form a thin film, which is then covered by an aqueous medium. The lipid film is hydrated to form MLVs, typically with sizes between about 0.1 to 10 microns. Other established liposomal formulation techniques may be applied as necessary. For example, the use of liposomes to facilitate cellular uptake is described in US Patents 4,897,355 and 4,394,448. Dosages Generally, when administered orally to a human, the SSRI dosage is usually around 0.001 to 200 mg per day, desirably about 1 to 100 mg per day, and more desirably about 5 to 50 mg per day. Dosages of up to 200 mg per day may become necessary. For administration of the SSRI by injection, the dosage is usually about 1 to 250 mg per day, desirably about 5 to 200 mg per day, and more desirably about 10 to 150 mg per day. Injections are desirably given one to four times daily. When systematically administered to a human, the dosage of the corticosteroid for use in combination with the SSRI is usually about 0.1 to 1,500 mg per day, desirably about 5 to 10 mg per day, and more desirably about 0.5 to 5. mg per day. The administration of each drug in the combination can, independently, be from one to four times daily for a day to a year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. Additional Applications The compounds of the invention can be used in immuno-modulatory or mechanistic assays to determine whether other combinations, or simple agents, are as effective as the combination in inhibiting the secretion or production of pro-inflammatory cytokines or modulating the immune response using assays generally known in the art, examples of which are described herein. For example, candidate compounds can be combined with an SSRI (or one of its metabolites or analogues) or a corticosteroid and applied to stimulated PBMCs. After a suitable time, the cells are examined for secretion or cytokine production or other suitable immune response. The relative effects of the combinations with each other, and against the simple agents are compared, and effective compounds and combinations are identified. The combinations of the invention are also useful tools for elucidating mechanistic information about the biological trajectories involved in inflammation. Such information may lead to the development of new combinations or simple agents to inhibit inflammation caused by pro-inflammatory cytokines. Methods known in the art for determining biological trajectories can be used to determine the trajectory, or network of trajectories, affected by contacting cells stimulated to produce pro-inflammatory cytokines with the compounds of the invention. Such methods may include, analyzing cellular constituents that are expressed or repressed after contact with the compounds of the invention as compared to untreated control compounds, positive or negative, and / or new simple agents and combinations, or analyzing some other activity metabolic of the cell such as enzyme activity, nutrient uptake, and proliferation. The cellular components analyzed can include gene transcripts, and protein expression. Suitable methods may include standard biochemistry techniques, radiolabel the compounds of the invention (e.g., labeled 14C or 3H), and observe the ligand compounds to proteins, e.g., using 2d gels, profiling the expression of gels Once identified, such compounds can be used in in vivo models to further validate the tool or develop new anti-inflammatory agents. The following examples are to illustrate the invention. They do not intend to limit the invention in any way. Example 1: Assay for pro-inflammatory cytokine suppressor activity Dilution matrices of compounds were tested for the suppression of IFNy, IL-? Β, IL-2, IL-4, IL-5, and TNFa, as described below . IFNy A suspension of 100 μ? of diluted human white blood cells contained within each well of a 384 well polystyrene plate (NalgeNunc) was stimulated to secrete IFNY by treatment with a final concentration of 10 ng / mL of phorbol 12-myristate 13-acetate (Sigma, P-1585) and 750 ng / mL of ionomycin (Sigma, 1-0634). Various concentrations of each test compound were added to the stimulation time. After 16-18 hours of incubation at 37 ° C in a humidified incubator, the plate was centrifuged and the supernatant was transferred to a 384 well plate of opaque white polystyrene (NalgeNunc, Maxisorb) coated with an anti-IFNy antibody (Endogen, # M-700A-E). After a two-hour incubation, the plate was washed (Tecan PowerWasher 384) with phosphate buffered saline (PBS) containing 0.1% T in 20 (polyoxyethylene-sorbitan monolaurate) and incubated for an additional hour with another anti-IFNy antibody that was labeled biotin (Endogen, M701B) and horseradish peroxidase (HRP) coupled to estrepavidin (PharMingen, # 13047E). After the plate was washed with 0.1% Tween 20 / PBS, a HRP-luminescent substrate was added to each well and the light intensity was measured using a LJL Analyst plate luminometer. IL-? ß A suspension of 100 μ? of diluted human white blood cells contained within each well of a 384 well polystyrene plate (NalgeNunc) was stimulated to secrete IL-? ß by treatment with a final concentration of 2 pg / mL liposaccharide (Sigma L-4130). Various concentrations of each test compound were added to the stimulation time. After 16-18 hours of incubation at 37 ° C in a humidified incubator, the plate was centrifuged and the supernatant was transferred to a 384 well plate of opaque white polystyrene (NalgeNunc, axisorb) coated with an anti-IL-antibody. ? ß (R &D, # MAB-601). After a two-hour incubation, the plate was washed (Tecan Power asher 384) with PBS containing 0.1% Tween 20 and incubated for an additional hour with another anti-IL-? Β antibody that was labeled biotin (R &D). , BAF-201) and HRP coupled to estrepavidin (PharMingen, # 13047E). After the plate was washed with 0.1% Tween 20 / PBS, a HRP-luminescent substrate was added to each well and the light intensity was measured using a LJL Analyst plate luminometer. IL-2 A suspension of 100 μ? of diluted human white blood cells contained within each well of a 384-well polystyrene plate (NalgeNunc) was stimulated to secrete IL-2 by treatment with a final concentration of 10 ng / mL of phorbol 12-myristate 13-acetate (Sigma , P-1585) and 750 ng / mL of ionomycin (Sigma, 1-0634). Various concentrations of each test compound were added to the stimulation time. After 16-18 hours of incubation at 37 ° C in a humidified incubator, the plate was centrifuged and the supernatant was transferred to a 384 well plate of opaque white polystyrene (NalgeNunc, Maxisorb) coated with an anti-IL-2 antibody. (PharMingen, # 555051). After a two hour incubation, the plate was washed (Tecan PowerWasher 384) with PBS containing 0.1% Tween 20 and incubated for an additional hour with another anti-IL-2 antibody that was labeled biotin (Endogen, M600B) and HRP coupled to estrepavidin (PharMingen, # 13047E). After the plate was washed with 0.1% Tween 20 / PBS, a HRP-luminescent substrate was added to each well and the light intensity was measured using a LJL Analyst plate luminometer. IL-4 and IL-5 The cytokine expression assay of IL-4 and IL-5 was carried out using the BD PharMingen Cytometric 6 Bead Array system according to the manufacturer's instructions. Briefly, the supernatant from a pigtail test plate was incubated with the tagged cytokine detection bill cocktail. The samples were then washed, resuspended and read on the BD Pharmingen FACsCalibur flow cytometer. The data was then analyzed using the BD Pharmingen CBA 6 Bead Analysis software. TNFa A suspension of 100 μ? of diluted human white blood cells contained within each well of a 384-well polystyrene plate (NalgeNunc) was stimulated to secrete TNFra by treatment with a final concentration of 2 ug / mL of liposaccharide (Sigma L-4130). Various concentrations of each test compound were added to the stimulation time. After 16-18 hours of incubation at 37 ° C in a humidified incubator, the plate was centrifuged and the supernatant was transferred to a 384 well plate of opaque white polystyrene (NalgeNunc, Maxisorb) coated with an anti-TNFa antibody (PharMingen, # 551220). After a two hour incubation, the plate was washed (Tecan Po erWasher 384) with PBS containing 0.1% Tween 20 and incubated for an additional hour with another anti-IL-? Β antibody that was labeled biotin (PharMingen, # 554511) and HRP coupled to estrepavidin (PharMingen, # 13047E). After the plate was washed with 0.1% Tween 20 / PBS, a HRP-luminescent substrate was added to each well and the light intensity was measured using a LJL Analyst plate luminometer. Example 2: Preparation of Compounds Solutions of material containing a corticosteroid or an SSRI were made in dimethylsulfoxide (DMSO) at a final concentration of between 0 and 40 μ. Master plates were prepared to contain dilutions of the material solutions of the compounds described above. The master plates were sealed and stored at -20 ° C until ready for use. The final simple agent plates were generated by transferring 1 pL of material solution from the specific master plate to a dilution plate containing 100 μ? of media (RPMI; Gibco BRL, # 11875-085), 10% fetal bovine serum (Gibco BRL, # 25140-097), 2% Penicillin / Streptomycin (Gibco BRL, # 15140-122)) using the Packer Mini-Trak liquid handler . This dilution plate was then mixed and an aliquot of 5 μL was transferred to the final assay plate, which had been pre-filled with 50 pL / well of RPMI medium containing the appropriate stimulant to activate a secretion of IFNy, IL- ? ß, IL-2, or TNFOI (see Example 1, supra). Example 3: Test of SSRIs, analogues, and metabolites for pro-inflammatory cytokine suppressor activity Single agents were tested for the ability to suppress secretion of IFNy, IL-β, IL-2, and TNFα from white blood cells stimulated, and the percentage inhibition of cytokine secretion, in relation to stimulated white blood cells, was determined. The data is shown in Tables 5-14, below.

Table 5 - Fl oxetine Table 6 - Fluvoxamine (μ?) TNFa TNFa IL-2 IL-? ß (μ?) IFNY (PI) (LPS) 63 90 76 90 39 39.27 46.16 1.5 55 0 33 25 19.64 10.07 5.75 26 0 6 7 9.82 5.6 .875 11 0 0 6 4.91 -0.75 .938 0 0 0 0 2.45 -2.92 .969 0 0 0 0 1.23 -1.66 .984 0 0 0 0 0.61 -0.05 .492 0 0 0 0 0.31 1.61 .246 0 0 0 0. 0.15 1.39 .123 0 0 0 0 0.08 -0.45 .062 0 0 0 0 0.04 2.14 .031 0 0 0 0 0.02 -3.52 Table 7 - Paroxetine Table 8 - Sertraline (μ?) TNFa TNFa IL-2 IL-? ß (μ) IFNY (PI) (LPS) 4.00 95 97 71 95 37.43 20 2.00 96 84 63 55 18.72 9 6.00 87 20 53 11 9.36 8 8. 00 66 7 36 6 4.68 6 4. 00 38 0 9 0 2.34 3 2. 00 18 0 0 0 1.17 4 1. 00 11 0 0 0 0.58 7 0. 50 0 0 0 0 0.29 5 0. 25 0 0 0 0 0.15 2 0. 13 0 0 0 0 0.07 1 0. 06 0 0 0 0 0.04 3 0. 03 0 0 0 0 0.02 1 Table 9 - Venlafaxine Table 10 - Norfluoxetine (μ?) TNFa TNFa IL-2 IL-? ß (PI) (LPS) 45.00 96 70 77 68 22. 50 86 0 66 0 11. 25 57 0 32 0 . 63 22 0 14 0 2. 81 0 0 7 0 1. 41 0 0 0 0 0. 70 0 0 0 0 0. 35 0 0 0 0 0. 18 0 0 0 0 0. 09 0 0 0 0 0. 04 0 0 0 0 0. 02 0 0 0 0 Table 11 - R (+) Fluoxetine (μ?) ??? to TNFa IL-2 IL-? ß (??) (LPS) 58 97 82 72 68 29 89 0 72 0 4.5 66 0 55 0 .25 22 0 11 0 .625 3 0 15 0 .813 0 0 12 0 .906 0 0 0 0 .453 0 0 0 0 .227 0 0 0 0 .113 0 0 0 0 .057 0 0 0 0 .028 0 0 0 0 Table 12 - S (+) Fluoxetine (μ?) TKTFa TNFa IL-2 IL-? B (??) (LPS) 58 98 72 62 76 29 94 45 66 70 4.5 70 0 55 31 .25 48 0 17 0 .625 20 0 0 0 .813 18 0 0 0 .906 12 0 0 0 .453 6 0 0 0 .227 7 0 0 0 .113 0 0 0 0 .057 0 0 0 0 .028 0 0 0 0 Table 13 - Zimeldina Example 4: Test of SSRIs for TNFa Suppressor Activity Combinations of SSRIs and corticosteroids were tested i) (t? Pμaroxena for the ability to suppress TNFa secretion from stimulated white blood cells, and the percentage inhibition of secretion from cytokine, in relation to stimulated untreated white blood cells, was determined.The data are shown in Tables 15-22.

Prednisolone (μ?) 0.400 0.200 0.100 0.050 0.025 0.013 0.006 0.003 0.0015 0.000 S.000 74.3 73.2 71.6 70.7 67.4 65.2 64.0 62.4 61.7 57.7 3. 000 55. 54.8 50.1 46.3 39.5 36.5 30.4 28.5 2S.4 22.8 1. 500 48.9 47.7 40.0 35.4 31.6 21.8 18.8 16.4 13.1 10.8 0. 750 43.6 43.2 35.5 31.0 23.0 17.7 11.9 9.4 5.82 4.0 0. 375 40.2 38.7 33. S 26.6 22.4 15.2 12.0 5.5 3.2 1.4 0. 188 38.1 38.8 32.1 26.4 19.8 16.5 9.3 5.4 1.5 -0.2 0. 094 42.3 38.5 30.6 25.8 21.3 14.4 9.8 4.1 4.9 -1.0 0. 047 37.6 37.5 31.6 28.2 16.5 12.1 6.4 3.B 0.2 -4.3 0. 023 37.1 35.3 32.1 23.4 18.5 9.35 4.5 1.3 -0.3 -3.1 0. 000 3S.2 34.1 29.4 23.4 16.5 11.5 4.6 -0.1 -0.8 -2.0 i () Pt? aroxenaμ Table 16 Prednisolone (μ?) 0.200 0.100 0.050 0.025 0.013 0.006 0.003 0.0015 0.0008 0.000 7. 230 64.0 52.9 54.7 43.5 43.9 42.4 36.1 31.6 31.4 29.6 3. 615 52.5 44.5 38.4 30.9 23.1 22.7 16.3 14.9 12.1 10.8 1. S08 47.0 42.0 36.8 31.5 22.7 19.8 13.4 19.3 13.4 12.

E 0.21 -8.9 8.6 8.1 21.2 27.6 30.9 36.1 39.9 40.5 a < aunt 0.42 1.4 4.0 9.8 17.5 29.4 34.6 38.9 38.3 45.6 OJ X 0.83 3.2 8.3 18.8 26.2 30.6 33.8 39.8 42.2 44.2 0 1.70 13.8 13.5 24.7 36.4 33.2 46.1 55.3 50.3 49.5 3. 30 29.1 47.8 50.3 56.3 55.2 60.5 62.3 67.0 66.2 6. 70 65.5 59.2 72.3 74.9 76.3 77.8 80.4 80.4 78.5 13. 00 88.2 88.3 90.0 89.0 92.8 92.3 92.5 88.5 92.4 27. 00 96.9 96.9 95.3 95.7 91.4 96.4 97.7 97.7 97.4 Table 22 The ability of the combination of prednisolone paroxetine to suppress the secretion of IL-4 and IL-5 in vitro was also tested. The results are shown in Tables 23 and 24. Table 23 - IL-4% Prednisolone Inhibition 1.0 μ? 47.76 Paroxetine 28.0 μ? 97.06 Combination (1.0 / 28.0) 97.32 Prednisolone 0.125 μ? 43.62 Paroxetine 3.5 m 43.64 Combination (0.125 / 3.5) 64.69 Prednisolone 0.016 μ? 18.53 Paroxetine 0.44 μ? 14.04 Combination (0.016 / 0.44) 18.10 Table 24 - IL-5 Example 5: The combination of cyclosporin A and sertraline reduces the secretion of IL-2 in vivo. The IL-2 secretion was measured by ELISA as described above after stimulation with phorbol 12-myristate 13-acetate and ionomycin. The effects of varying concentrations of cyclosporin A, sertraline and a combination of sertraline and cyclosporin A were compared with control wells. These wells were stimulated with phorbol 12-myristate 13-acetate and ionomycin, but did not receive cyclosporin A or sertraline. The results of this experiment are shown in Table 25. The effects of the agents alone and in combination are shown as percent inhibition of IL-2 secretion.

Table 25 Example 6: The combination of cyclosporin A and sertraline reduces the secretion of IFNy in vitro The IFNy secretion was measured by ELISA as described above after stimulation with phorbol 12-myristate 13-acetate and ionomycin. The effect of varying concentrations of cyclosporin A, sertraline and cyclosporin A in combination with sertraline A was compared with stimulated control wells without cyclosporin A or sertraline. The results of this experiment are shown in Table 26, below. The effects of the agents alone and in combination are shown as percent inhibition of IFNv secretion.

Table 26 % Inhibition of IFNy PBMC PI Cyclosporin A (μ?) Example 7: The composition of cyclosporin A and sertraline reduces the secretion of TNFOI in vitro The TNFOI secretion was measured by ELISA as described above after stimulation with phorbol 12-myristate 13-acetate and ionomycin. The effect of varying concentrations of cyclosporin A, sertraline and cyclosporin A in combination with sertraline were compared with stimulated control wells without cyclosporin A or sertraline. The results are shown in Table 27, below. The effects of the agents alone and in combination are shown as percent inhibition of IFNY secretion.

Table 27 % Inhibition of TNFa PB C PI Cyclosporin A (μ?) Example 8: The combination of cyclosporin A and fluoxetine reduces secretion of IL-2 in vitro. IL-2 secretion was measured by ELISA as described above after stimulation with phorbol 12-myristate 13-acetate and ionomycin. The effect of varying concentrations of cyclosporin A, fluoxetine and cyclosporin A in combination with fluoxetine were compared with stimulated control wells without cyclosporin A or fluoxetine. The results are shown in Table 28, below. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion.

Table 28 Example 9: The combination of tacrolimus and fluvoxamine reduces the secretion of IL-2 in vi tro The IL-2 secretion was measured by ELISA as described above after stimulation with phorbol 12-myristate 13-acetate and ionomycin. The effect of varying concentrations of tacrolimus, fluvoxamine, and tacrolimus in combination with fluvoxamine were compared with stimulated control wells without tracrolimus or fluvoxamine. The results are shown in Table 29, below. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion.Table 29 % Inhibition of IL-2 PB C PI Tacrol mus (μ?) Example 10: The combination of cyclosporin A and fluoxetine reduces secretion of IL-2 in vitro. IL-2 secretion was measured by ELISA as described above after stimulation with phorbol 12-myristate 13-acetate and ionomycin. The effect of varying concentrations of cyclosporin A, paroxetine and cyclosporin A in combination with paroxetine were compared with stimulated control wells without cyclosporin A or paroxetine. The results are shown in Table 30, below. The effects of the agents alone and in combination are shown as a percentage of inhibition of IL-2 secretion.

Table 30 Other Forms of Embodiment Various modifications and variations of the system method of the invention described will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it should be understood that the invention as claimed should not be unduly limited to such embodiments. Indeed, various modifications of the modes described for carrying out the invention that are obvious to those skilled in the art of medicine, immunology, pharmacology, endocrinology, or related fields are intended to be within the scope of the invention.

Claims (77)

1. CLAIMS 1.
2. A composition comprising a selective serotonin reuptake inhibitor (SSRI) and a corticosteroid in amounts which together are sufficient in vivo to decrease the secretion or production of pro-inflammatory cytokine.
3. The composition of claim 1, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanodotiepin, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, milnacipram, paroxetine, sertraline, tametralin, viqualine, or zimeldin The composition of claim 1, wherein said corticosteroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorasone.
4. The composition of claim 1, wherein said SSRI is fluoxetine or paroxetine and said corticosteroid is prednisolone.
5. The composition of claim 1, wherein said SSRI or said corticosteroid is present in said composition in a low dose.
6. The composition of claim 1, wherein said SSRI or said corticosteroid is present in said composition in a high dose.
7. The composition of claim 1, further comprising an NSAID, biological COX-2 inhibitor, DMARD, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analog, psoralen , retinoid, and 5-amino salicylic acid.
8. The composition of claim 7, wherein said NSAID is ibuprofen, diclofenac, or naproxen.
9. The composition of claim 7, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.
10. The composition of claim 7, wherein said biological is adelimumab, etanercept, or infliximab.
11. The composition of claim 7, wherein said DMARD is methotrexate or leflunomide.
12. 12. The composition of claim 7, wherein said xanthine is theophylline.
13. The composition of claim 7, wherein said anti-cholinergic compound is ipratropium or tiotropium.
14. The composition of claim 7, wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol escetate, salmeterol xinafoate, or terbutaline.
15. The composition of claim 7, wherein said non-steroidal calcineurin inhibitor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247.
16. 16. The composition of claim 7, wherein said vitamin D analog is calcipotriene or calcipotriol.
17. 17. The composition of claim 7, wherein said psoralen is methoxsalen.
18. The composition of claim 7, wherein said retinoid is acitretin or tazoretene.
19. The composition of claim 7, wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, balsalazi-disodium, or olsalazine sodium.
20. The composition of claim 1, wherein said composition is formulated for topical administration.
21. The composition of claim 1, wherein said composition is formulated for systemic administration.
22. 22. A method for decreasing the secretion or production of pro-inflammatory cytokine in a patient, said method comprising administering to the patient an SSRI and a corticosteroid simultaneously or within 14 days to each other in sufficient quantities in vivo to decrease secretion or Pro-inflammatory cytokine production in said patient.
23. 23. A method for treating a patient diagnosed with, or at risk of developing, an immuno-inflammatory disorder, said method comprising administering to the patient an SSRI and a corticosteroid simultaneously or within 14 days of each other in sufficient amounts to treat to said patient.
24. The method of claim 23, wherein said immuno-inflammatory disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymylagia, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, severe myiastemia, psoriasis, ankylosing spondylitis, or psoriatic arthritis.
25. The method of claim 23, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanodotiepin, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, milnacipram, paroxetine, sertraline, tametralin, viqualine, or zimeldin 26.
26. The method of claim 23, wherein said corticosteroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone, or diflorasone.
27. The method of claim 23, further comprising administering to said patient an NSAID, biological COX-2 inhibitor, DMARD, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analogue , psoralen, retinoid, and 5-amino salicylic acid.
28. The method of claim 27, wherein said NSAID is ibuprofen, diclofenac, or naproxen.
29. 29. The method of claim 27, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.
30. 30. The method of claim 27, wherein said biological is adelimumab, etanercept, or infliximab.
31. 31. The method of claim 27, wherein said DMARD is methotrexate or leflunomide.
32. 32. The method of claim 27, wherein said xanthine is theophylline.
33. 33. The method of claim 27, wherein said anti-cholinergic compound is ipratropium or tiotropium.
34. 34. The method of claim 27, wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol esceptate, salmeterol xinafoate, or terbutaline.
35. 35. The method of claim 27, wherein said non-steroidal calcineurin inhibitor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247.
36. 36. The method of claim 27, wherein said vitamin D analog is calcipotriene or calcipotriol.
37. 37. The method of claim 27, wherein said psoralen is methoxsalen.
38. 38. The method of claim 27, wherein said retinoid is acitretin or tazoretene.
39. 39. The method of claim 27, wherein said 5-amino salicylic acid is mesalamine, sulfasalazine, disodium balsalazi-da, or sodium olsalazine.
40. 40. The method of claim 23, wherein said SSRI or said corticosteroid is administered in a low dose.
41. 41. The method of claim 23, wherein said SSRI or said corticosteroid is administered in a high dose.
42. 42. The method of claim 23, wherein said SSRI and said corticosteroid are administered within 10 days of each other.
43. 43. The method of claim 42, wherein said SSRI and said corticosteroid are administered within five days together.
44. 44. The method of claim 43, wherein said SSRI and said corticosteroid are administered within twenty-four hours together.
45. 45. The method of claim 44, wherein said SSRI and said corticosteroid are administered simultaneously.
46. 46. A composition comprising an SSRI and a glucocorticoid receptor modulator in amounts that together are sufficient to decrease the secretion or production of pro-inflammatory cytokine.
47. 47. The composition of claim 46, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanodotypi na, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, milnacipram, paroxetine, sertraline, tametralin , viqualina, or zimeldina.
48. 48. The composition of claim 46, further comprising a compound selected from the group consisting of MSAID, biological COX-2 inhibitor, DMARD, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, inhibitor. of non-steroidal calcineurin, vitamin D analogue, psoralen, retinoid, and 5-amino salicylic acid.
49. 49. A method for decreasing the secretion or production of pro-inflammatory cytokine in a patient, said method comprising administering to a patient an SSRI and a glucocorticoid receptor modulator simultaneously or within 14 days to each other in sufficient amounts in vivo to decrease the secretion production of pro-inflammatory cytokine in said patient.
50. 50. A method for treating a patient diagnosed with, or at risk of developing, an immuno-inflammatory disorder, said method comprising administering to the patient an SSRI and a glucocorticoid receptor modulator simultaneously or within 14 days to each other in amounts enough to treat that patient.
51. 51. The method of claim 50, wherein said immuno-inflammatory disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymylagia, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis. , severe myiastemia, psoriasis, ankylosing spondylitis, or psoriatic arthritis.
52. 52. The method of claim 50, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanodotiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, milnacipram, paroxetine, sertraline, tametralin, viqualine, or zimeldin.
53. 53. The method of claim 50, further comprising administering to said patient an NSAID, biological COX-2 inhibitor, DMARD, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, non-steroidal calcineurin inhibitor, vitamin D analogue , psoralen, retinoid, and 5-amino salicylic acid.
54. 54. The method of claim 50, wherein said SSRI and said glucocorticoid receptor modulator are administered within 10 days of each other.
55. 55. The method of claim 54, wherein said SSRI and said glucocorticoid receptor modulator are administered within five days together.
56. 56. The method of claim 55, wherein said SSRI and said glucocorticoid receptor modulator are administered within twenty-four hours together.
57. 57. The method of claim 56, wherein said SSRI and said glucocorticoid receptor modulator are administered simultaneously.
58. 58. A pharmaceutical composition comprising (i) an SSRI and (ii) a second compound selected from the group consisting of a xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilizer, biological, NSAID, DMARD, COX inhibitor. -2, non-steroidal calcineurin inhibitor, vitamin D analogue, psoralen, retinoid, and 5-amino salicylic acid.
59. 59. The composition of claim 58, wherein said NSAID is ibuprofen, diclofenac, or naproxen.
60. 60. The composition of claim 58, wherein said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or lumiracoxib.
61. 61. The composition of claim 58, wherein said biological is adelimumab, etanercept, or infliximab.
62. 62. The composition of claim 58, wherein said DMARD is methotrexate or leflunomide.
63. 63. The composition of claim 58, wherein said xanthine is theophylline.
64. 64. The composition of claim 58, wherein said anti-cholinergic compound is ipratropium or tiotropium.
65. 65. The composition of claim 58, wherein said beta receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol esceptate, salmeterol xinafoate, or terbutaline.
66. 66. The composition of claim 58, wherein said nonsteroidal calcineurin inhibitor is cyclosporin, tacrolimus, pimecrolimus, or ISAtx247.
67. 67. The composition of claim 58, wherein said vitamin D analog is calcipotriene or calcipotriol.
68. 68. The composition of claim 58, wherein said psoralen is methoxsalen.
69. 69. The composition of claim 58, wherein said retinoid is acitretin or tazoretene.
70. 70. A method for suppressing the secretion of one or more pro-inflammatory cytokines in a patient in need thereof, said method comprising administering to the patient (i) an SSRI and (ii) a second compound selected from the group consisting of a xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, biologic, NSAID, DMARD, COX-2 inhibitor, non-steroidal calcineurin inhibitor, vitamin D analog, psoralen, retinoid, and 5-amino-salicylic acid in sufficient amounts in I live to decrease the secretion or production of pro-inflammatory cytokine in said patient.
71. 71. A method for suppressing the secretion of one or more pro-inflammatory cytokines in a patient in need thereof, said method comprising administering to the patient an SSRI in an amount sufficient to suppress the secretion of pro-inflammatory cytokines in said patient.
72. 72. A method for treating a patient diagnosed with an immuno-inflammatory disorder, said method comprising administering to the patient an SSRI in an amount and for a duration sufficient to treat said patient.
73. 73. A kit, comprising: (i) a composition comprising an SSRI and a corticosteroid; and (ii) instructions for administering said composition to a patient diagnosed with, or at risk of developing, an immune-inflammatory disorder.
74. 74. A kit, comprising: (i) an SSRI; (ii) a corticosteroid; and (iii) instructions for administering said SSRI and said corticosteroid to a patient diagnosed with, or at risk of developing, an immuno-inflammatory disorder.
75. 75. A kit comprising (i) an SSRI and (ii) instructions for administering said SSRI to a patient diagnosed with an immuno-inflammatory disorder.
76. 76. A kit, comprising: (i) an SSRI; (ii) a second compound selected from the group consisting of a glucocorticoid receptor modulator, xanthine, anti-cholinergic compound, beta receptor agonist, bronchodilator, biological, NSAID, DMARD, COX-2 inhibitor, calcineurin inhibitor, steroidal, vitamin D analogue, psoralen, retinoid, and 5-amino salicylic acid; and (iii) instructions for administering said SSRI and said second compound to a patient diagnosed with, or at risk of developing, an immuno-inflammatory disorder.
77. 77. A method for identifying combinations of compounds useful for suppressing the secretion of pro-inflammatory cytokines in a patient in need of such treatment, said method comprising the steps of: (a) contacting cells in vitro with an SSRI and a compound candidate; and (b) determining whether the combination of said SSRI and said candidate compound reduces cytokine levels in blood cells stimulated to secrete cytokines relative to cells contacted with said SSRI but not contacted with said candidate compound or cells. placed in contact with said candidate compound but not with said SSRI, where a reduction of said cytokine levels identifies said combination as a combination that is useful for treating a patient in need of such treatment.