HK1092058A - Treatment of depression and other affective disorders - Google Patents

Description

Treatment of depression and other affective disorders

Technical Field

The present invention relates to the use of gaboxadol (gaboxadol) for the preparation of a medicament for the treatment of depression. The invention also relates to the use of gaboxadol in combination with a 5-hydroxytryptamine reuptake inhibitor (SRI), or any other compound that results in an increase in extracellular 5-hydroxytryptamine levels, for the treatment of depression and other affective disorders.

Background

Gaboxadol (THIP), described in both EP patent 0000338B1 and EP patent 0840601B1, shows great potential in the treatment of sleep disorders.

Selective 5-hydroxytryptamine reuptake inhibitors (hereinafter SSRIs) are the drug of choice in the treatment of certain forms of depression, anxiety and social phobia, because of their efficacy, better tolerability and good safety profile compared to traditional tricyclic antidepressants.

However, clinical studies of depression and anxiety disorders have shown considerable non-responsiveness to SSRJs, up to 30%. Another factor that is often overlooked in anti-depression therapy is compliance, which has a strong effect on the patient's motivation to continue drug therapy.

Disclosure of Invention

According to the present invention, a pharmaceutical composition for the treatment of depression is provided.

Gaboxadol has the formula

And throughout the specification "gaboxadol" is meant to include any form of the compound, such as the base (zwitterion), a pharmaceutically acceptable salt, for example, a pharmaceutically acceptable acid addition salt, a hydrate or solvate of the base or salt, and an anhydrate, as well as amorphous or crystalline forms.

More particularly, the present invention relates to the use of gaboxadol having the general formula in the preparation of a pharmaceutical composition for the treatment of depression.

In a still further aspect, the invention relates to a method of treating depression comprising administering to a subject in need thereof a pharmaceutically acceptable amount of gaboxadol. The individual is preferably a human, such as a male or female, child, adult or elderly person.

According to the present invention gaboxadol may be used in the form of the base (zwitter ion) or a pharmaceutically acceptable acid addition salt thereof or an anhydrate or hydrate of such a salt or base. The salts of the compounds used in the present invention are in the form of salts with non-toxic organic or inorganic acids. Examples of such organic salts are the salts with the following acids: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and 8-halotheophylline, for example 8-bromotheophylline. Examples of such inorganic salts are: hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate. Gaboxadol may also be used in the form of a zwitter ion, e.g. its simple hydrate.

The process for the preparation of the acid addition salts of the present invention may comprise treatment of gaboxadol with an acid in an inert solvent followed by precipitation, isolation and optional recrystallisation using known methods and if desired micronisation of the crystallised product by wet or dry milling or other convenient means, or preparation of particles by solvent emulsification processes. Suitable processes are described in EP patent 0000338.

The precipitation of the salt is typically carried out in an inert solvent, for example an inert polar solvent such as an alcohol (e.g., ethanol, 2-propanol, and n-propanol), although water or a mixture of water and an inert solvent may also be used.

In a particular embodiment gaboxadol is used in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate. In a further embodiment, gaboxadol is used in the form of a pharmaceutically acceptable acid addition salt selected from: hydrochloric acid or hydrobromic acid salt, or in the form of a zwitter-ionic monohydrate. Most conveniently, gaboxadol is in crystalline form.

According to the invention, gaboxadol may be administered in any suitable manner, e.g. orally or parenterally, and it may be formulated for such administration in any suitable form, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection. Preferably, gaboxadol is administered as a solid pharmaceutical entity, suitably in the form of a tablet or capsule, or a suspension, solution or dispersion for injection according to the invention.

Methods for preparing solid pharmaceutical formulations are well known in the art. Tablets may thus be prepared by mixing the active ingredient with conventional adjuvants and/or diluents and subsequently compressing the mixture in a suitable tablet press. Examples of adjuvants or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive compatible with the active ingredient, such as a coloring agent, a fragrance, a preservative, etc., may be used.

Suitable formulation forms of gaboxadol are described in WO 02/094225 filed on 2002, 5/17.

It should be understood that any aspect or embodiment of the present patent application is not intended to limit the present invention in any way, and is a suitable embodiment of the medicament or pharmaceutical composition herein.

Gaboxadol is typically administered by oral dosage forms, such as solid oral dosage forms, typically tablets or capsules, or as liquid oral dosage forms. Gaboxadol is most conveniently administered in an oral unit dosage form, such as a tablet or capsule, containing the active ingredient in an amount of from about 0.1 to about 150 mg/day, for example from about 0.1 to about 100 mg/day, typically from about 0.5 to about 50 mg/day, preferably from about 2.5 to about 20 mg/day, for example from about 5 to about 15 mg/day. The amount of gaboxadol is calculated as the free base.

Gaboxadol may be administered as monotherapy or in combination therapy with other drugs. In particular, gaboxadol may be combined with a 5-hydroxytryptamine reuptake inhibitor as described below.

Combination of gaboxadol with a 5-hydroxytryptamine reuptake inhibitor

In addition, gaboxadol may be used to enhance and provide faster production of therapeutic effects of 5-hydroxytryptamine reuptake inhibitors, particularly citalopram and escitalopram.

It has surprisingly been found that gaboxadol can be used to enhance and provide faster onset of therapeutic effect of 5-hydroxytryptamine reuptake inhibitors.

In one aspect, the invention relates to the use of gaboxadol for preparing a pharmaceutical composition for use in combination with a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine levels.

In another aspect, the invention relates to the use of gaboxadol for preparing a pharmaceutical composition for enhancing and/or providing a faster onset of therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor or any other compound that results in an increase in extracellular 5-hydroxytryptamine levels.

In a further aspect, the invention relates to a pharmaceutical composition or kit comprising gaboxadol and a compound which is a 5-hydroxytryptamine reuptake inhibitor or any other compound which results in an increase in extracellular 5-hydroxytryptamine levels, and optionally a pharmaceutically acceptable carrier or diluent.

In a further aspect, the invention relates to a method of treating a disease or disorder (disorders) responsive to an inhibitor of 5-hydroxytryptamine reuptake or any other compound capable of causing an increase in extracellular 5-hydroxytryptamine levels, comprising administering gaboxadol and the inhibitor of 5-hydroxytryptamine reuptake, or a compound capable of causing an increase in extracellular 5-hydroxytryptamine levels, to a subject in need of such treatment.

In a further aspect, the invention relates to the use of gaboxadol and a compound which is a 5-hydroxytryptamine reuptake inhibitor or any other compound capable of causing an increase in extracellular 5-hydroxytryptamine levels for the preparation of a pharmaceutical composition for the treatment of a disease or disorder responsive to the therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor or any other compound capable of causing an increase in extracellular 5-hydroxytryptamine levels.

In a further aspect, the invention relates to the use of gaboxadol for preparing a pharmaceutical composition for treating a subject who is about to receive or is receiving treatment with a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine levels, wherein the subject has a disease or disorder responsive to the therapeutic effect of the 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine levels.

In a further aspect, the invention relates to the use of gaboxadol and a compound wherein the compound is a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine level for the manufacture of a kit for the treatment of a disease or disorder responsive to the therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine level.

In a further aspect, the present invention relates to a method for enhancing and/or providing a faster onset of therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor or any other compound which causes an increase in extracellular 5-hydroxytryptamine levels, comprising administering gaboxadol to a subject who is about to receive or is receiving treatment with a 5-hydroxytryptamine reuptake inhibitor or any other compound which causes an increase in extracellular 5-hydroxytryptamine levels. Such individuals are preferably humans, such as males or females, children, adults or elderly.

In one embodiment, the 5-hydroxytryptamine reuptake inhibitors or compounds which cause an increase in extracellular 5-hydroxytryptamine levels are used for the treatment of depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, thymic dysfunction, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.

In still further embodiments, 5-hydroxytryptamine reuptake inhibitors or compounds that cause elevated extracellular 5-hydroxytryptamine levels are used to treat anxiety disorders, including generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder, or social anxiety disorder.

In still further embodiments, the 5-hydroxytryptamine reuptake inhibitor is selected from the group consisting of: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), sertraline (sertraline), paroxetine (parooxetine), fluvoxamine (fluvoxamine), venlafaxine (venlafaxine), duloxetine (duloxetine), dapoxetine, nefazodone (nefazodone), imipramin (imipramin), famoxatin (femoxetine) and clomipramine (clomipramine) or any pharmaceutically acceptable salts of these compounds. Merely by way of illustration, each of the 5-hydroxytryptamine reuptake inhibitors specifically mentioned above is intended as a separate embodiment. Accordingly, any of them and their use may be claimed separately.

In a still further embodiment, the 5-hydroxytryptamine reuptake inhibitor is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI).

In a further embodiment, the pharmaceutical composition or kit prepared is suitable for simultaneous administration of the active ingredients. In one embodiment, the active ingredients are contained in the same unit dosage form.

In a further embodiment, the pharmaceutical composition or kit prepared is suitable for sequential administration of the active ingredients. In one embodiment, the active ingredients are contained in separate unit dosage forms.

In a further aspect, the invention relates to the use of gaboxadol for preparing a pharmaceutical composition for use in combination with a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine levels.

In particular, the invention relates to the use of gaboxadol for preparing a pharmaceutical composition for enhancing and/or providing a faster onset of therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor or any other compound that results in an increase in extracellular 5-hydroxytryptamine levels.

More particularly, the present invention relates to the use of gaboxadol as described above together with a 5-hydroxytryptamine reuptake inhibitor or any other compound which causes an increase in extracellular 5-hydroxytryptamine levels in the treatment of depression, anxiety disorders and other affective disorders, such as general anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post traumatic stress disorder and social anxiety disorder, eating disorders, such as bulimia, anorexia and obesity, phobias, thymic dysfunction, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, especially depression.

The anxiety disorder includes generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder or social anxiety disorder.

As used herein, the term enhancing includes improving the therapeutic effect and/or potentiating the therapeutic effect of SRI or a compound that causes an increase in extracellular 5-HT levels.

In a further embodiment, the invention relates to the use of a compound which is a gaboxadol and a 5-hydroxytryptamine reuptake inhibitor, or a compound which causes an increase in extracellular 5-hydroxytryptamine level, for the manufacture of a pharmaceutical composition for the treatment of a disease or disorder responsive to the therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor, or any other compound which causes an increase in extracellular 5-hydroxytryptamine level.

In a further embodiment, the invention relates to the use of a compound which is a gaboxadol and a 5-hydroxytryptamine reuptake inhibitor, or a compound which causes an increase in extracellular 5-hydroxytryptamine levels, in the manufacture of a kit-of-parts (kit) for the treatment of a disease or disorder responsive to the therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor, or any other compound which causes an increase in extracellular 5-hydroxytryptamine levels.

Diseases that respond to 5-hydroxytryptamine reuptake inhibitors include: depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, thymic dysfunction, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, in particular depression.

The term anxiety disorder is as defined above.

In one embodiment, the present invention relates to the use of gaboxadol for preparing a pharmaceutical composition as described hereinbefore, which is suitable for simultaneous administration of the active ingredients. In particular, the pharmaceutical compositions may contain the active ingredient in the same unit dosage form, e.g., in the same tablet or capsule. Such unit dosage forms may contain the active ingredient in a homogeneous mixture or in separate compartments of the unit dosage form.

In another embodiment, the invention relates to the use of gaboxadol for preparing a pharmaceutical composition or kit as described above, which is suitable for sequential administration of the active ingredients. In particular, such pharmaceutical compositions may contain the active ingredients in separate unit dosage forms, such as separate tablets or capsules each containing either active ingredient. Such separate unit dosage forms may be contained in the same container or package, e.g., a blister pack.

As used herein, the term kit refers to a pharmaceutical composition containing each active ingredient, but in separate unit dosage forms.

The invention also relates to a pharmaceutical composition or kit comprising gaboxadol and a 5-hydroxytryptamine reuptake inhibitor compound, or any other compound that results in an increase in extracellular 5-HT levels, and optionally a pharmaceutically acceptable carrier or diluent.

As mentioned above, the pharmaceutical composition or kit of the invention may be adapted for simultaneous administration of the active ingredients or for sequential administration of the active ingredients.

Finally, the present invention relates to a method of treating a disease or disorder responsive to a 5-hydroxytryptamine reuptake inhibitor or any other compound capable of causing an increase in extracellular 5-hydroxytryptamine levels, comprising administering gaboxadol and the 5-hydroxytryptamine reuptake inhibitor, or a compound capable of causing an increase in extracellular 5-HT levels, to a subject in need thereof.

In particular, the present invention relates to a method for enhancing and/or providing a faster onset of therapeutic effect of a 5-hydroxytryptamine reuptake inhibitor or any other compound capable of causing an increase in extracellular 5-hydroxytryptamine levels, comprising administering gaboxadol to a subject prepared for or undergoing treatment with a 5-hydroxytryptamine reuptake inhibitor or any other compound capable of causing an increase in extracellular 5-hydroxytryptamine levels.

Those individuals who would benefit from the combination therapy described above may suffer from depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, premenstrual syndrome, thymic dysfunction, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse, particularly depression.

As mentioned above, anxiety disorders include generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, acute stress disorder, post-traumatic stress disorder or social anxiety disorder.

As noted above, gaboxadol and the 5-hydroxytryptamine reuptake inhibitor may be administered simultaneously.

Alternatively, the active ingredients may be administered sequentially, for example, in two separate unit dosage forms as described above.

At present, it has been surprisingly found that co-administration of gaboxadol and a 5-hydroxytryptamine reuptake inhibitor results in a significantly increased response in an anti-depressive effect prediction animal model, a mouse forced swimming test, compared to the administration of the 5-hydroxytryptamine reuptake inhibitor alone.

As described above, 5-hydroxytryptamine reuptake inhibitors exhibit delayed onset of action. Even in SSRIs responders, several weeks of treatment are required to achieve symptom relief. Gaboxadol achieves a faster onset of therapeutic effect of the 5-hydroxytryptamine reuptake inhibitor.

The use of gaboxadol in combination with a 5-hydroxytryptamine reuptake inhibitor significantly reduces the amount of 5-hydroxytryptamine reuptake inhibitor required to treat depression and other affective disorders, and thus reduces the side effects associated with 5-hydroxytryptamine reuptake inhibitors. In particular, the combination of reduced amounts of SRI and gaboxadol may reduce the risk of sexual dysfunction and sleep disturbance by SSRI.

Gaboxadol co-administered with a 5-hydroxytryptamine reuptake inhibitor is also useful in the treatment of refractory depression, i.e., depression that is not properly treated by the 5-hydroxytryptamine reuptake inhibitor alone. Typically, gaboxadol is used as an augmentation therapy (add-on therapy) to enhance responses to SRIs in those patients who fail to achieve at least 40-60% reduction in symptoms during the first 6 weeks of treatment with SRI.

Typically, gaboxadol may be used in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate. In a still further embodiment gaboxadol is used in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate. Most conveniently, gaboxadol is used in crystalline form.

Many antidepressants having a 5-hydroxytryptamine reuptake inhibiting effect have been described in the literature. Any pharmacologically active compound that exerts its therapeutic effect, either predominantly or in part, by inhibiting the re-uptake of 5-hydroxytryptamine by the Central Nervous System (CNS) may benefit from the potentiating effect of gaboxadol.

The following list includes a number of 5-hydroxytryptamine reuptake inhibitors that may benefit from the potentiation of gaboxadol: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluxetine), R-fluoxetine (R-fluxetine), sertraline (sertraline), paroxetine (parooxetine), fluvoxamine (fluvoxamine), venlafaxine (venlafaxine), duloxetine (duloxetine), dapoxetine, nefazodone (nefazodone), imipramine (imipramin), imipramine N-oxide (imipramin N-oxide), desipramine (desipramine), piradamine (piradamine), daradamine (pirandamine), dapzetidine (dazine), nefopramine (nefofeprazine), nefozepam (nefopramine), befluazulene (nefopramine), befluquinazine (bexaline), fezolamide (fexopramine), moxifloxacilline (moxifloxacilline), cloxacilline (loxapine), pefloxacin (369852), fluquinamine (wurtymene (wurtzitine, flufenadine (Woxipramine, mexiline (e), fluquinacrine (e, flufenadine (e), fluquinacrine (e, fluquinacrine, flufenadine (e, fluquinacrine, fluacrine (e, fluacrine (fluacrine, fluacrine, propyl alapamide (alanoglclate), cyclanothiopine, trimipramine (trimipramine), quinupramine (quinupropramine), dithiazepine (dothien), amoxapine (amoxapine), nitrozapine, McN 5652, McN 5707, O177, Org 6582, Org 6997, Org 6906, amitriptyline (amitriptyline), amitriptyline N-oxide (amitriptyline N-oxide), nortriptyline (nortriptyline), CL 255.663, pirlindole (piendole), indtriptyline (indatriline), LY 113.821, 214.281, CGP 6085A, RU 25.591, nepaferazole (naphazoline), diazaspirine (diclosenine), trazodone (trazodone), EMD 68.843, Y42.569, cyclanopine (crotonone), clonidine (clonidine ), clonidine (clavulane), clonidine (clavulanine, clavulanine (clavulanine), clavulanine (clavulanine, clavulanine (s, clavulanine,

n- [ (1- [ (6-fluoro-2-naphthalene) methyl ] -4-piperidinyl ] amino ] carbonyl ] -3-pyridinecarboxamide, [ trans-6- (2-chlorophenyl) -1, 2, 3, 5, 6, 10 b-hexahydropyrrolo- (2, 1-a) isoquinolin ] (McN 5707),

(rac-4-exo-amino-8-chloro-benzo- (b) -bicyclo [3.3.1] nona-2-6 α (10 α) -diene hydrochloride) (Org 6997),

(rac) - (5 α, 8 α, 9 α) -5, 8, 9, 10-tetrahydro-5, 9-methylenebenzocycloocten-8-amine hydrochloride (Org 6906),

- [2- [4- (6-fluoro-1H-indol-3-yl) -3, 6-dihydro-1 (2H) -pyridinyl ] ethyl ] -3-isopropyl-6- (methylsulfonyl) -3, 4-dihydro-1H-2, 1, 3-benzothiadiazine-2, 2-dioxide (LY393558), [4- (5, 6-dimethyl-2-benzofuranyl) -piperidine ] (CGP 6085),

dimethyl- [5- (4-nitro-phenoxy) -6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-7-yl ] -amine (RU 25.591),

the above compounds may be used in the form of a base or a pharmaceutically acceptable salt, for example, an acid addition salt thereof. Each of the 5-hydroxytryptamine reuptake inhibitors described above is a separate embodiment. Accordingly, each of them and their uses may be claimed individually.

Other therapeutic compounds that may benefit from the potentiating effect of gaboxadol include those that, while not 5-hydroxytryptamine reuptake inhibitors, cause an increase in extracellular 5-hydroxytryptamine levels in synaptic clefts. One such compound is tianeptine.

The above list of 5-hydroxytryptamine reuptake inhibitors and other compounds that cause an increase in extracellular 5-hydroxytryptamine levels may not be construed as limiting.

In a specific embodiment, the SRIs are selected from: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), sertraline (sertraline), paroxetine (parooxetine), fluvoxamine (fluvoxamine), duloxetine (duloxetine), venlafaxine (venlafaxine), duloxetine (duloxetine), dapoxetine, nefazodone (nefazodone), imipramin (imipramin), femoxetine and clomipramine (clomipramine). Merely by way of illustration, each SRIs constitutes a separate embodiment and may be the subject of individual claims.

The term selective 5-hydroxytryptamine reuptake inhibitor (SSRI) refers to an inhibitor of the monoamine transporter which has a greater inhibitory effect on the 5-hydroxytryptamine transporter than on the dopamine and norepinephrine transporters.

Selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) are one of the most preferred 5-hydroxytryptamine reuptake inhibitors for use in the present invention. Thus, in a further embodiment, the SRI is selected from SSRIs, for example: citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluoxetine), fluvoxamine (fluvoxamine), sertraline (sertraline), or paroxetine (parooxetine).

The active ingredients of the invention, such as gaboxadol and SRI or a compound that causes an increase in extracellular 5-hydroxytryptamine levels, may be used in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof, the latter being prepared by reacting the base form with a suitable acid.

Citalopram (citalopram) is preferably used as the hydrobromide or base, escitalopram (escitalopram) as the oxalate, fluoxetine (fluooxetine), sertraline (sertraline) and paroxetine (parooxetine) as the hydrochloride and fluvoxamine (fluvoxamine) as the maleate.

As described above, the combination of gaboxadol and a 5-hydroxytryptamine reuptake inhibitor unexpectedly exhibits a synergistic effect on the CNS. As a result, the combination therapy of gaboxadol with a lower dose of the 5-hydroxytryptamine reuptake inhibitor than is conventionally used in monotherapy can be very effective, while the side effects caused by the larger amount of the 5-hydroxytryptamine reuptake inhibitor used in monotherapy can be reduced or completely prevented.

Furthermore, combination therapy with gaboxadol with a conventional dose of a 5-hydroxytryptamine reuptake inhibitor has the advantage that effective CNS effects can be achieved in those patients who are often refractory to conventional monotherapy with SSRIs in large numbers.

The amount of gaboxadol used in the combination therapy may range from about 0.1 to about 150 mg/day, such as from about 0.1 to about 100 mg/day, from about 0.5 to about 50 mg/day, from about 5 to about 50 mg/day, or from about 1 to about 5 mg/day. Low dose gaboxadol combination therapy with a 5-hydroxytryptamine reuptake inhibitor, such as escitalopram (escitalopram), without significant effect on sleep disorders shows a clear and significant effect. A low dose is typically selected from about 0.1 to about 2.5 mg/day, for example from about 0.1 to about 2.0 mg/day, while a higher dose is typically selected from about 2.5 to about 150 mg/day.

5-hydroxytryptamine reuptake inhibitors include the SSRIs specifically mentioned above, which differ in their molecular weight and activity. Thus, the amount of 5-hydroxytryptamine reuptake inhibitor used in the combination therapy depends on the identity of the 5-hydroxytryptamine reuptake inhibitor. In a particular embodiment of the invention, the 5-hydroxytryptamine reuptake inhibitor or the compound capable of causing an increase in extracellular 5-HT levels is administered in an amount which is less than the dose required for the individual use of said compound. In another embodiment, the 5-hydroxytryptamine reuptake inhibitor or compound that causes an increase in extracellular 5-HT levels is administered in a conventional dosage.

To prepare the pharmaceutical compositions of the invention, an appropriate amount of the active ingredient, in salt form or base form, is mixed with a pharmaceutically acceptable carrier in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions may be in a unit dosage form suitable for oral, rectal, transdermal or parenteral administration. For example, in preparing the compositions in oral dosage form, any of the conventional pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, and the like in oral liquid preparations, such as suspensions, syrups, elixirs, and solutions; alternatively, in powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed. Because of their ease of administration, tablets and capsules represent the best oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.

The pharmaceutical compositions described above are particularly advantageous when formulated in unit dosage forms for ease of administration and consistent dosage. As used in the specification and claims, unit dosage form (unit dosageform) refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a desired pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Gaboxadol may be administered before, during, or after administration of the 5-hydroxytryptamine reuptake inhibitor, provided that the time interval between administration of gaboxadol and administration of the 5-hydroxytryptamine reuptake inhibitor allows for a synergistic effect of the ingredients on the CNS. A composition containing a 5-hydroxytryptamine reuptake inhibitor and gaboxadol may be particularly convenient when gaboxadol and the 5-hydroxytryptamine reuptake inhibitor are administered simultaneously. Alternatively, gaboxadol and the 5-hydroxytryptamine reuptake inhibitor may be administered separately in a suitable composition. The composition may be prepared as described above.

The invention also includes products containing gaboxadol and a 5-hydroxytryptamine reuptake inhibitor as a combined preparation for simultaneous, separate or sequential use in psychiatric treatment. Such products may include, for example, kits comprising separate unit dosage forms containing gaboxadol and separate unit dosage forms containing the 5-hydroxytryptamine reuptake inhibitor, all contained in the same container or package, e.g., a blister pack.

The above-mentioned formulations for simultaneous or sequential administration may be free of 5-hydroxytryptamine reuptake inhibitors and may contain other compounds which cause an increase in extracellular 5-HT levels.

Pharmacological experiment of anti-depression effect of gaboxadol

The rat Chronic Mild Stress (CMS) model of depression has a high degree of predictive accuracy for antidepressant activity (Willner (1997), Psychopharmacol 134: 319-329). In addition, this method is an appropriate model for studying the effect of antidepressant activity in animals (Behavioural Pharmacology 14: 465-470, 2003, S.nchez, C.et al). The principle of this model is based on the correlation between stress and affective disorders. Rats with chronic stress exhibit reduced sensitivity to rewards (e.g., palatable sucrose solutions).

Experimental method for chronic mild pressure

Male Wistar rats (Gorzkowska, Warsaw) were brought into the laboratory two months before the start of the experiment. The animals were kept individually, water and food were ingested freely, and were maintained for a 12h light/dark cycle at a temperature of 22. + -. 2 ℃ except as described below.

First training animals to consume 1% sucrose solution; training consisted of 81 h baseline experiments with sucrose feeding in the squirrel cage during the experiment followed by 14h without water and food; intake was measured by weighing previously weighed bottles of sucrose solution at the end of the experiment. Subsequently, sucrose consumption was monitored throughout the experiment under similar conditions. Animals were divided into two matched groups based on their sucrose intake in the final baseline experiment. One group of animals underwent a chronic mild stress course for 8 consecutive weeks. The weekly pressure regime consists of: 2 cycles of no food or water feeding, 45 degree inclination of the squirrel cage, intermittent illumination (light on and off every 2h), soiling of the cages (250 ml water in sawdust bedding), placing two in one cage and low intensity stroboscopic illumination (150 flashes/min), and 2 cycles of no pressure. All stressors lasted 10-14h and were applied daily and overnight separately and continuously. Other groups of animals, no pressure control, were housed in additional rooms and were not exposed to animals under pressure. Animals were not fed food and water for 14h prior to each sucrose experiment, but in addition food and water were freely ingested in the cages. After experiencing 3 weeks stress, the stress and control animals were divided into matched subgroups according to their sucrose intake scores, and received two daily injections of peritoneal drug (at about 10.00 and 17.00) over the following 5 weeks. Sucrose experiments were performed on a weekly basis at 10 am (tuesday). Animals in different groups (n-8) were dosed with vehicle (1ml/kg daily) or experimental drug. The drug was administered at about 10.00h prior to the experimental period, and a sucrose experiment was performed 24h after the previous drug injection. The pressure is maintained continuously throughout the treatment cycle. And body weight was assessed at baseline at the end of drug treatment.

Chronic mild stress results

The experiment of gaboxadol in a rat chronic mild stress model shows that the compound has a significant anti-depression-like effect. In this model, a dose of 2.5mg/kg per day had a clear and significant effect.

Combination of gaboxadol with escitalopram

To modulate the activity of the system responsible for antidepressant activity, we investigated the interaction of gaboxadol with escitalopram, an SSRI, in a model of 5-hydroxytryptamine reuptake inhibition behavior, a mouse 5-HTP boost test, and a model of predicting antidepressant activity, a mouse forced swim test (see C.S a nchez et al, Psychopharmacology (2003), 167: 353-362).

Experimental procedure

Male NMRI/BOM mice (18-25 g; Bomholtgaard, Denmark) were selected. Mice were housed in plastic cages (35X 30X 12cm) of 10 mice per cage, and were familiarized with animal facilities at least one week prior to the experiment. Room temperature (21. + -. 2 ℃ C.), relative humidity (55. + -. 5%) and air exchange (16 times per hour) was regulated automatically. Animals were free to ingest commercial food particles and tap water prior to the experiment.

Potentiation of 5-HTP-induced behavior

The experimental procedures for mouse studies are described in detail in Hyttel et al (1992). Briefly, mice were administered 5-HTP (100mg/kg, i.v.) 30 minutes after the administration of the test compound s.c. The animals were then evaluated for stereotypy (lateral cephalic movement), tremor, and hind limb abduction in cages at a 15-min observation period. One point is given for the appearance of one symptom. A total of 8-16 mice were used per dose.

Suppression of immobility caused by forced swimming

A mouse forced to swim in a spatially restricted container will exhibit a typical immotile posture. Pretreatment with antidepressants will counteract this effect. The experiments were carried out as described in detail in the S-nchez and Meier literature (Psychopharmacol 129: 197-205; 1997). Briefly, a fully automated experimental system with 6 swimming units (2000 ml glass jars with 1200ml dirty water (23-25 ℃) in which mice are pre-loaded) was used. The motionless state is evaluated by image analysis. After 30 minutes of drug or vehicle treatment of the mice, they were placed in a glass jar and the mice were allowed to stand in water for a total of 6 minutes. The cumulative duration of immobility was measured over the last 3 minutes. A total of 9-18 mice were used per dose.

Results

In the 5-HTP potentiation experiment, gaboxadol (2.5mg/kg) strongly potentiates the acute effect of escitalopram (0.5 to 0.025mg/kg), and the dose of gaboxadol (2.5mg/kg), which itself has no effect in the forced swim experiment, significantly potentiates the antidepressant-like effect of escitalopram (2.5 and 5 mg/kg).

Claims (46)

1. A method of treating depression comprising administering to a subject in need thereof a pharmaceutically acceptable amount of gaboxadol.

2. The method of claim 1 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.

3. The method of any one of claims 1-2 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.

4. The method of any one of claims 1-3, wherein the pharmaceutically acceptable amount is in the range of 2.5mg to 20mg, such as 5mg to 15mg gaboxadol per day.

5. The method of any one of claims 1-4 wherein gaboxadol is administered as an oral dosage form.

6. The method of any one of claims 1-5 wherein gaboxadol is in a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.

7. The method of any one of claims 1-6 wherein the gaboxadol is crystalline.

8. The method of any one of claims 1-7, wherein the individual is a human.

9. Use of gaboxadol for the preparation of a pharmaceutical composition for the treatment of depression.

10. The use of claim 9 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.

11. The use of any one of claims 9 to 10 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.

12. The use of any one of claims 9-11, wherein the pharmaceutical composition comprises from 2.5mg to 20mg, such as from 5mg to 15mg, of gaboxadol.

13. The use of any one of claims 9-12 wherein gaboxadol is in an oral dosage form.

14. The use of any one of claims 9-13 wherein gaboxadol is in a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.

15. The use of any one of claims 9-14 wherein the gaboxadol is crystalline.

16. The use of any one of claims 9-15, wherein the pharmaceutical composition is for treating a human suffering from depression.

17. Use of gaboxadol for preparing a pharmaceutical composition for use in combination with a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine levels.

18. Use of gaboxadol for preparing a pharmaceutical composition for enhancing and/or providing a faster 5-hydroxytryptamine reuptake inhibitor or any other therapeutic effect of a compound that results in an increase in extracellular 5-hydroxytryptamine levels.

19. Use of gaboxadol for preparing a pharmaceutical composition for treating a subject prepared for, or being treated with, a 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine level, wherein the subject has a disease or disorder responsive to the therapeutic effect of the 5-hydroxytryptamine reuptake inhibitor or any other compound that causes an increase in extracellular 5-hydroxytryptamine level.

20. The use as claimed in any one of claims 17 to 19, wherein the 5-hydroxytryptamine reuptake inhibitor or the compound capable of causing an increase in extracellular 5-hydroxytryptamine levels is used for the treatment of depression, anxiety disorders and other affective disorders, eating disorders such as bulimia, anorexia and obesity, phobias, thymic dysfunction, premenstrual syndrome, cognitive disorders, impulse control disorders, attention deficit hyperactivity disorder and drug abuse.

21. The use as claimed in claim 20, wherein the 5-hydroxytryptamine reuptake inhibitor or the compound capable of causing an increase in extracellular 5-hydroxytryptamine levels is used in the treatment of depression.

22. The use of any one of claims 17 to 21, wherein the 5-hydroxytryptamine reuptake inhibitor is selected from the group consisting of: citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, famoxadine and clomipramine or a pharmaceutically acceptable salt of any of these compounds.

23. The use of any one of claims 17 to 22, wherein the 5-hydroxytryptamine reuptake inhibitor is a selective 5-hydroxytryptamine reuptake inhibitor.

24. The use of any one of claims 17 to 23 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.

25. The use of any one of claims 17 to 24 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.

26. The use of any one of claims 17-25 wherein the pharmaceutical composition comprises gaboxadol in an amount between about 0.1 to about 2.5 mg.

27. The use of any one of claims 17-25 wherein the pharmaceutical composition comprises gaboxadol in an amount from between about 2.5mg to about 20 mg.

28. The use of any one of claims 17-27 wherein gaboxadol is in an oral dosage form.

29. The use of any one of claims 17 to 28, wherein the 5-hydroxytryptamine reuptake inhibitor or the compound capable of causing an increase in extracellular 5-hydroxytryptamine levels is in an oral dosage form.

30. The use of claim 28 wherein gaboxadol is in a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.

31. The use of claim 29, wherein the 5-hydroxytryptamine reuptake inhibitor or the compound capable of causing an increase in extracellular 5-hydroxytryptamine levels is in a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.

32. The use of any one of claims 17-31 wherein gaboxadol is crystalline.

33. The use of any one of claims 17-32 wherein the pharmaceutical composition is suitable for simultaneous administration of gaboxadol and the 5-hydroxytryptamine reuptake inhibitor.

34. The use of any one of claims 17-33 wherein gaboxadol and the 5-hydroxytryptamine reuptake inhibitor are contained in the same unit dosage form.

35. The use of any one of claims 17-34 wherein the pharmaceutical composition is suitable for sequential administration of gaboxadol and the 5-hydroxytryptamine reuptake inhibitor.

36. A pharmaceutical composition comprising gaboxadol and a 5-hydroxytryptamine reuptake inhibitor compound, or any other compound that results in an increase in extracellular 5-hydroxytryptamine levels, optionally together with a pharmaceutically acceptable carrier or diluent.

37. The pharmaceutical composition of claim 36, wherein the 5-hydroxytryptamine reuptake inhibitor is selected from the group consisting of citalopram, escitalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, venlafaxine, duloxetine, dapoxetine, nefazodone, imipramine, famoxatin and clomipramine or a pharmaceutically acceptable salt of any of these compounds.

38. The pharmaceutical composition of any one of claims 36-37, which is suitable for the simultaneous administration of gaboxadol and the 5-hydroxytryptamine reuptake inhibitor.

39. The pharmaceutical composition of any one of claims 36-38 wherein gaboxadol and the 5-hydroxytryptamine reuptake inhibitor are contained in the same unit dosage form.

40. The pharmaceutical composition of any one of claims 36-39 wherein gaboxadol is in the form of an acid addition salt, or a zwitter ion hydrate or zwitter ion anhydrate.

41. The pharmaceutical composition of any one of claims 36-40 wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.

42. The pharmaceutical composition of any one of claims 36-41 wherein gaboxadol is present in an amount from about 0.1 to about 2.5 mg.

43. The pharmaceutical composition of any one of claims 36-41 wherein gaboxadol is present in an amount from about 2.5 to about 20 mg.

44. The pharmaceutical composition of any one of claims 36-43, wherein gaboxadol is in an oral dosage form, such as a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.

45. The pharmaceutical composition of any one of claims 36-44, wherein the 5-hydroxytryptamine reuptake inhibitor is an oral dosage form, such as a solid oral dosage form, such as a tablet or capsule, or a liquid oral dosage form.

46. The pharmaceutical composition of any one of claims 36-45 wherein gaboxadol is crystalline.