WO2002076461A1

WO2002076461A1 - Combination of reboxetine and citalopram

Info

Publication number: WO2002076461A1
Application number: PCT/GB2001/001336
Authority: WO
Inventors: Serdar Murat Dursun; Sivakumaran Devarajan
Original assignee: Serdar Murat Dursun; Sivakumaran Devarajan
Priority date: 2001-03-26
Filing date: 2001-03-26
Publication date: 2002-10-03

Abstract

A composition comprising, in combination: a) a pharmaceutically effective amount of reboxetine or a pharmaceutically effective salt thereof; and b) a pharmaceutically effective amount of citalopram or a pharmaceutically effective salt thereof is provided. The composition is useful in treating disorders of diseases of the central nervous system and particularly useful in treating treatment-resistant depression.

Description

COMBINATION OF REBOXETINE AND CITALOPRAM AND THERAPEUTIC METHOD

BACKGROUND OF THE INVENTION Field of the Invention

The invention describes new treatments that provide relief from nervous system disorders with reduced side effects. More particularly, the invention involves the administration of a selective norepinephrine reuptake inhibitor (SNRI), reboxetine, in combination with a selective serotonin reuptake inhibitor (SSRI), citalopram. Description of Related Technology

The introduction of tricyclic antidepressants in the early 1960s has provided a major advance in the treatment of neuropsychiatric disorders. Reactive and endogenous depressions, diagnoses formerly carrying grave prognostic implications, have become, with the introduction of the tricycics, manageable disorders with a much smaller toll on the patient population and society as a whole.

The early tricyclic compounds were reuptake inhibitors of all the catecholamines released in the synaptic cleft, thus resulting in prolongation and enhancement of the dopamine (DA), noradrenaline (NA) and serotonin (5-hydroxytryptamine= 5-HT) action. The lack of selectivity also caused undesired side effects, particularly on the acetylcholine (especially the muscarinic component), and histamine-mediated neurotransmission. Undesirable pharmacodynamic activities, cognitive impairment, sedation, urinary and gastrointestinal tract disturbances, and increased intraocular pressure proved to be limiting factors in the clinical use of tricyclic compounds. The cardiac toxic effects and proconvulsant activity of the tricyclic compounds also caused great concern among clinicians. As a result, treatment with tricyclic compounds largely has been discontinued.

Selective norepinephrine reuptake inhibitors have been introduced as an alternative to tricyclic compounds for use in the treatment of depression. Lower than- normal levels of norepinephrine are associated with many symptoms of depression, including lack of energy, motivation, and interest in life. Thus, a normal level of norepinephrine is essential to maintaining drive and capacity for reward. The norepinephrine neurotransmitters travel from the terminal end of a neuron across a small gap (i.e the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. The binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport (i.e. reuptake) of the neurotransmitter back into the presynaptic neuron. Abnormality in noradrenergic transmission results in various types of depression, mental, behavioural, and neurological disorders attributed to a variety of symptoms including a lack of energy, motivation, and interest in life. See generally, R.J. Baldessarini, "Drugs and the Treatment of Psychiatric Disorders: Depression and Mania" in Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, NY, NY, pp. 432-439 (1996).

One commercially available norepinephrine reuptake inhibitor is the compound reboxetine. Reboxetine is disclosed in U.S. Patent No. 4,229,449, and is commercially available from Pharmacia & UpJohn Company (also known as Pharmacia Corporation), Kalamazoo, Michigan, U.S.A., under the trade name EDRONAX®. Methods of preparing the compound, as well as dosing and administration guidelines also are available in the literature. For example, methods of preparing the compound are described in U.S. Patent Nos. 5,068,433 and 5,391 ,735. A method for administering reboxetine and other antidepressant active agents is described in Canadian Family Physician, 45: 2663-2668 (1994).

Another class of active agents, selective reuptake inhibitors for serotonin (SSRI), also have been introduced with definite advantages in regard to fewer side effects without loss of efficacy. One commercially available SSRI is the compound citalopram, which is available from Forest Pharmaceuticals, Inc., St. Louis Missouri, U.S.A., under the trade name CELEXA® (citalopram hydrobromide). The citalopram compounds, as well as methods of preparing the compound are described in U.S. Patent No. 4,136,193.

Reboxetine and citalopram have demonstrated activity in treating and relieving symptoms of nervous system disorders, particularly in the treatment of mood disorders. Examples of mood disorders include, but are not limited to, panic disorder, post- traumatic stress disorder, social anxiety disorder, dysthymic disorder, generalised anxiety disorders, and other phobias and mood-affecting disorders.

The treatment of nervous system disorders also has been plagued by the recent onset of new disorders, the symptoms of which are resistant to conventional treatments. A patient suffering from major depressive disorder (MDD), for example, typically demonstrates unsatisfactory response to multiple types of traditional therapies administered at optimal dosage and for an optimal period of time. Such traditional therapies can include, for example, treatment with tricyclic compounds, SSRIS alone, reboxetine alone or in combination with lithium, and augmentation with lithium. The benefits of multiple active agents previously have been reported. There exists some recognition in the art that antidepressant active agents having the dual activity of serotonergic and noradrenergic effect are successful in treating resistant types of depression. See, Depression and Anxiety, 7(1): 5-6 (1998). Certain combinations of active agents having antidepressant activity also have been reported. For example, it has been described in the literature that patients who fail to respond to an SSRI inhibitor can be administered a selective norepinephrine reuptake inhibitor, such as reboxetine, to augment ongoing SSRI therapy. See, Hum. Psychopharmacol. Clin. Exp., 15:143-145 (2000). Although the combination of active agents can provide a beneficial therapeutic alternative when compared with the traditional therapies, the clinical practice of such combined therapy can be unpredictable and there remains a need to provide new methods of treating resistant types of depression with relatively low amounts of side effects.

In view of the foregoing, it would be desirable to develop a pharmaceutical composition that demonstrates beneficial therapeutic effect in the treatment of a variety of nervous system disorders, including major depressive disorder or other nervous system disorders characterized by symptoms that are resistant to traditional therapies. In particular, it would be particularly beneficial for the desired therapy to provide such beneficial therapeutic effect with reduced side effects. Summary of the Invention

In accordance with the invention, a pharmaceutical composition is provided. More specifically, the composition combines a reboxetine active agentwith a citalopram active agent to provide a therapeutically effective composition. The treatment is considered to be particularly effective against treatment-resistant depression. A first embodiment of the invention provides a composition comprising, in combination: (a) a pharmaceutically effective amount of reboxetine or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of citalopram or a pharmaceutically effective salt thereof.

In particularly preferred embodiments, component (a) comprises reboxetine in either its enantiomeric form, preferably the (S.S)-enantiomer, or in its racemic form.

Another embodiment of the invention provides a method for treating or preventing diseases or disorders of the central nervous system comprising administering a therapeutically effective amount of the above composition to a mammal.

In many instances, the mammal will be a human, and the disease or disorder to be treated is treatment-resistant depression. A further embodiment of the invention comprises the use of the above composition to prepare a medicament for treating or preventing diseases or disorders of the central nervous system.

The composition of the invention also can be used in the manufacture of a medicament. The medicament can be used for treating or preventing diseases or disorders of the central nervous system.

The invention also provides a method for treating or preventing diseases of the central nervous system by using the compositions of the invention. The composition and method of the invention provides an effective treatment for treatment-resistant depression.

These and other aspects, advantages, and features of the invention will become apparent from the following detailed description of the invention. Detailed Description of the Invention

In describing the invention, certain terminology will be utilized for the sake of clarity. Such terminology is intended to encompass the invention, as well as all technical equivalents operating in a similar manner for a similar purpose to achieve a similar result.

The invention provides a composition. The composition is a combination of different chemical entities, more specifically, the first entity being reboxetine and the second being citalopram.

The first component is the norepinephrine reuptake inhibitor, reboxetine or a pharmaceutically effective salt thereof. Examples of pharmaceutically effective salts for reboxetine include, but are not limited to, salts prepared from pharmaceutically acceptable acids or bases, including organic and inorganic acids and bases. Pharmaceutically effective salts may be prepared from pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acids include acetic, benzenesulfonic

(besylate), benzoic, p-bromophenylsulfonic camphorsulfonic, carbonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, mandelic, methanesulfonic (mesylate), mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Examples of such pharmaceutically acceptable salts include, but are not limited to, acetate, benzoate, hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1,4- dioate, carpoate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1 ,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, naphthalene-1- sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylproionate, phosphate, phthalate, phylacetate, propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, and the like.

In particularly preferred embodiments, the selective norepinephrine reuptake inhibitor is reboxetine, 2-[α-((2-ethoxyphenoxy)benzyl]-morpholine, and its pharmaceutically acceptable salts, in either its enantiomeric (particularly the (S,S) enantiomer) or racemic form. Synthesis of racemic reboxetine is described in greater detail in U.S. Patent No. 4,229,449. Individual stereoisomers of reboxetine can be obtained by resolution of the racemic mixture of enantiomers using conventional methods generally known by those skilled in the art. Such methods include, but are not limited to, resolution by simple crystallization and chromatographic techniques, for example, as set forth in GB 2, 167,407. Other methods of preparation are described in U.S. Patent No. 5,068,433 and U.S. Patent No. 5,391 ,735. Reboxetine can be a free base form, or it can be in salt form, preferably the methanesulfonate salt (also called reboxetine mesylate). To the extent necessary for completion, the above patents are expressly incorporated by reference.

The selection of the dosage of the first component is that which can provide relief to the patient. As is well known, the dosage of the component depends on several factors such as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, the severity of the condition to be treated, and the like. This is considered to be within the skill of the artisan and one can review the existing literature on the components to determine optimal dosing. To the extent necessary for completion, the synthesis of the components and dosages described in the patents or documents referenced in the Technology Description portion of this document are expressly incorporated by reference.

When reboxetine is selected as the active agent, the daily dose contains from about 0.1 mg to about 12 mg. More preferably, each dose of the component contains about 0.5 to about 8 mg of the active ingredient, and even more preferably, each dose contains from about 2 mg to about 6 mg of the active ingredient. This dosage form permits the full daily dosage to be administered in one or two oral doses. This will allow for final formulations containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9. 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 mg of reboxetine. More than once daily or twice daily administrations (e.g. three, four, five, or six administrations per day) are also expressly contemplated herein. Pediatric dosages may be less.

The second component of the invention is the selective serotonin reuptake inhibitor, citalopram, or a pharmaceutically effective salt thereof. Citalopram is a racemic bicyclic phthalene derivative having the scientific name (±)-1-(3- dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, which has been described in U.S. Patent No.4,136,193. Pharmaceutically effective salts can be prepared as described herein for the first component reboxetine salts, except substituting citalopram for reboxetine. Particularly preferred salts of citalopram include, but are not limited to, the hydrobromide salt, i.e. citalopram hydrobromide. To the extent necessary for completion, the above patent is expressly incorporated by reference.

The daily dose of citalopram typically contains from about 0.1 mg to about 100 mg. More preferably, each dose of the component contains about 20 mg to about 80 mg of the active ingredient, and even more preferably, each dose contains from about 40 mg to about 60 mg of the active ingredient. This dosage form permits the full daily dosage to be administered in one or two oral doses. More than once daily or twice daily administrations (e.g. three, four, five, or six administrations per day) are also expressly contemplated herein. Pediatric dosages may be less than the described dosages and are well within the skill of one in the art, particularly considering the weight, age, and condition of the patient child.

As is well known, the dosage and administrative regimen (i.e., one, two, three or more administrations per day) of the second component depends on the factors referred to in connection with the dosage selection of the first component. To the extent necessary for completion, the synthesis of the components and dosages described in the patents or documents referenced in the Technology Description portion of this document are expressly incorporated by reference.

Compositions of the invention can conveniently be administered in a pharmaceutical composition containing the active components in combination with a suitable excipient. Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed., 1975). To the extent necessary for completion, this reference is hereby incorporated by reference. The compositions of the invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, intranasally, intravaginally, or rectally, with oral administration being particularly preferred.

For oral therapeutic administration, the inventive composition may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, foods and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 0.1 to about 100% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. The above listing is merely representative and one skilled in the art could envision other binders, excipients, sweetening agents and the like. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active components may be incorporated into sustained- release preparations and devices including, but not limited to, those relying on osmotic pressures to obtain a desired release profile. The inventive composition, containing the two active components, may be administered in the same physical form or concomitantly according to the above- described dosages and in the above-described delivery vehicles. The dosages for each active component can be measured separately and can be given as a single combined dose or given separately. They may be given at the same or at different times as long as both actives are in the patient at one time over a 24-hour period. Concomitant or concurrent administration means the patient takes one drug within about 5 minutes of taking the other drug. Because the goal is to provide rapid symptomatic relief to the patient, in most cases when treatment is started the two drugs would be administered to the patient close in time and typically concomitantly; thereafter, the timing of each drug's administration may not be as important.

A preferred embodiment of the invention involves administering reboxetine and citalopram concomitantly, either in the same carrier or in separate carriers, so that a daily amount of about 0.1 mg to about 12 mg reboxetine and about 0.1 mg to 100 mg citalopram is administered. The composition can contain, for example, about 0.5 mg to about 8 mg of reboxetine and about 20 mg to about 80mg citalopram, or more particularly, about 2 mg to about 6 mg reboxetine and about 40 mg to about 60 mg citalopram.

The inventive composition is used to treat any of the diseases or disorders of the central nervous system. Such diseases arid disorders are defined in The Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) (American Psychiatric Association (1995)). To the extent necessary for completion, the contents of this reference and all of the defined diseases or disorders are expressly incorporated by reference. Representative diseases or disorders include, but are not limited to the following: obesity, depression, schizophrenia, stress-related diseases (e.g. general anxiety disorder), panic disorders, phobias, obsessive compulsive disorders, post- traumatic-stress syndrome, immune system depression, incontinence, stress-induced problems with the urinary, gastrointestinal or cardiovascular system (e.g. stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorders and withdrawal syndrome, adjustment disorders, age-associated learning and mental disorders, anorexia nervosa, apathy, attention- deficit disorders due to general medical conditions, attention-deficit hyperactivity disorders, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorders, cyclothymic disorders, dysthymic disorders, fibromyalgia and other somatoform disorders, generalized anxiety disorders, inhalation disorders, intoxication disorders, movement disorders (e.g. Tourette's syndrome), oppositional defiant disorders, pain disorders, peripheral neuropathy, post-traumatic stress disorders, premenstrual dysphoric disorders, psychotic disorders, seasonal affective disorders, sleep disorders, specific developmental disorders, and selective serotonin reuptake inhibition (SSRI) "poop out" syndrome. More preferably, the treatment is used to prevent or reduce symptoms of panic disorders, post-traumatic stress disorders, depression, social anxiety disorders, dysthymic disorders, generalized anxiety disorders, and other phobias and mood-affecting disorders.

Treatment of the above diseases or disorders is accomplished by delivering a therapeutically effective amount of the inventive composition to a mammal. In most cases this will be a human being, but treatment of food animals (e.g. livestock and poultry) and companion animals (e.g. dogs, cats and horses) is expressly covered herein.

In particular, the inventive composition is to be used in the treatment of treatment-resistant depression. While not wishing to be bound to any specific scientific theory, it is believed that the addition of reboxetine to citalopram can significantly increase the effectiveness of treating resistant or refractory depression. Moreover, the novel composition is expected to provide rapid relief to those suffering from the above diseases or disorders with a minimal amount of deleterious side effects. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the invention to its fullest extent. The following detailed example describes how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Example 1

Ten patients (A-J) were evaluated in a study to determine the efficacy and safety of reboxetine (EDRONAX®, Pharmacia & UpJohn, Kalamazoo, Ml, U.S.A.) and citalopram (CELEXA®, Forest Labs, St. Louis, MO, U.S.A.) in combination fortreatment of treatment-resistant depression. The patients were identified as follows: Patient A: a 57-year-old male outpatient;

Patient B: a 45-year-old male inpatient;

Patient C: a 68-year-old female inpatient;

Patient D: a 48-year-old female inpatient;

Patient B; a 54-year-old female inpatient; Patient F: a 20-year-old female inpatient;

Patient G: a 34-year-old female inpatient;

Patient H: a 34-year-oId-male inpatient;

Patient I: a 42-year-old female inpatient; and

Patient J: a 50-year-old male outpatient. The baseline characteristics of the patients are shown in Table 1 , below. Table 1

Patients A-F only.

Patients had previously failed to respond satisfactorily to:

(i) at least two SSRIs (optimum dose and duration); (ii) a TCA; (iii) augmentation with lithium, T3 and psychotherapy;

(iv) venlafaxine (dose range 225-375 mg/day, maximum tolerated dose). Six patients (A-F) were treated with a combination of:

(i) citalopram at an initial dose of 20 mg/day titrated (over 4-8 weeks) to 60 mg/day;

(ii) reboxetine at an initial dose of 4 mg/day titrated (over 4-8 weeks) to 8 mg/day. Four patients (G-J) were treated with a combination of:

(ii) reboxetine at an initial dose of 4 mg/day titrated (over 4-8 weeks) to 6 mg/day.

At Week 8, patients were receiving citalopram 60 mg/day plus reboxetine

8 mg/day (6 patients) or 6 mg/day (4 patients). The 17-item Hamilton Depression Rating Scale (HAM-D) was used to monitor the clinical outcome. Adverse events were also recorded. Baseline Week 8 and Week 16 HAM-D total scores are shown in Table

2. Table 2

Patient HAM-D total scores²

Baseline Week 8 Week 16

A 32 15 3

B 30 12 4

C 28 10 3

D 30 16 12

E 32 14 10

F 36 20 8

G 32 16 4

H 34 6 4

1 26 12 7

J 24 10 6

² HAM-D total scores at Weeks 8 and 16 where 13.1 ±4 (SD) and 6.1 ±3.1 (SD), respectively. These scores were significantly different from baseline scores (p<0.05).

The data demonstrated that reboxetine plus citalopram can be beneficial in patients with refractory depression. The total HAM-D score improved in all patients.

The mean total HAM-D score improved significantly between baseline (31.3±2J) and Week 8 (14.5±3.5; p <0.05) with a further improvement by Week 16 (6J±3.9; p <0.05).

The combination of citalopram and reboxetine was well-tolerated by all patients.

The foregoing detailed description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the invention may become apparent to those skilled in the art without departing from the scope of the appended claims.

Claims

1. A composition comprising, in combination:

(a) a pharmaceutically effective amount of reboxetine or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of citalopram or a pharmaceutically effective salt thereof.

2. The composition according to claim 1, wherein component (a) is a (S,S)- enantiomer or a racemic form of reboxetine.

3. The composition according to claim 1, containing between about 0.1 mg to about 12 mg reboxetine.

4. The composition according to claim 1, containing between about 0.5 mg to about 8 mg reboxetine.

5. The composition according to claim 1 , containing between about 2 mg to about 6 mg reboxetine.

6. The composition according to claim 1, wherein component (b) is citalopram or a hydrobromide salt thereof.

7. The composition according to claim 1, containing between about 0.1 mg to about 100 mg citalopram.

8. The composition according to claim 1 , containing between about 20 mg to about 80 mg citalopram.

9. The composition according to claim 1 , containing between about 40 mg to about 60 mg citalopram.

10. The composition according to claim 1 , wherein component (a) and component (b) are maintained in the same delivery vehicle.

11. The composition according to claim 1 , wherein component (a) and component (b) are maintained in different delivery vehicles.

12. A method for treating a disease or disorder of the central nervous system in a mammal comprising administering to said mammal:

(a) a pharmaceutically effective amount of reboxetine or a pharmaceutically effective salt thereof; and

(b) a pharmaceutically effective amount of citalopram or a pharmaceutically effective salt thereof.

13. The method according to claim 12, wherein said disease or disorder is selected from the group consisting of obesity, depression, schizophrenia, stress-related diseases, panic disorder, phobias, obsessive compulsive disorders, post-traumatic- stress syndrome, immune system depression, stress-induced problems with the urinary, gastrointestinal or cardiovascular system, neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, incontinence, sexual dysfunction, addictive disorders, and withdrawal syndrome, adjustment disorders, age-associated learning and mental disorders, anorexia nervosa, apathy, attention-deficit disorders due to general medical conditions, attention-deficit hyperactivity disorders, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, conduct disorders, cyclothymic disorders, dysthymic disorders, fibromyalgia and other somatoform disorders, generalized anxiety disorders, inhalation disorders, intoxication disorders, movement disorders, oppositional defiant disorders, pain disorders, peripheral neuropathy, post-traumatic stress disorders, premenstrual dysphoric disorders, psychotic disorders, seasonal affective disorders, sleep disorders, specific developmental disorders, and selective serotonin reuptake inhibition (SSRI) "poop out" syndrome.

14. The method of claim 12, wherein said disease or disorder is selected from the group consisting of panic disorders, post-traumatic stress disorders, social anxiety disorders, dysthymic disorders, generalized anxiety disorders, and other phobias and mood-affecting disorders.

15. The method according to claim 12, wherein said disease or disorder comprises treatment-resistant depression.

16. The method of claim 12, wherein said composition is administered rectally, topically, orally, sublingually, intranasally, transdermally or parenterally.

17. The method according to claim 12, wherein component (a) and component (b) of said composition are administered as a single combination.

18. The method according to claim 12, wherein component (a) and component (b) of said composition are concomitantly administered.

19. The method according to claim 12, containing between about 0.1 mg to about 12 mg reboxetine.

20. The method according to claim 12, containing between about 0.5 mg to about 8 mg reboxetine.

21. The method according to claim 12, containing between about 2 mg to about 6 mg reboxetine.

22. The method according to claim 12, wherein component (b) is citalopram or a hydrobromide salt thereof.

23. The method according to claim 12, containing between about 0.1 mg to about 100 mg citalopram.

24. The method according to claim 12, containing between about 20 mg to about 80 mg citalopram.

25. The method according to claim 12, containing:

(a) between about 0.1 mg to about 12 mg citalopram reboxetine; and

(b) between about 0.1 mg to about 100 mg citalopram or citalopram hydrobromide.

26. A composition consisting essentially of; (a) a pharmaceutically effective amount of reboxetine in its racemic or enantiomeric form; and

27. The composition according to claim 26, wherein component (a) and component (b) of said composition are administered as a single combination.

28. The composition according to claim 26, wherein component (a) and component (b) of said composition are concomitantly administered.

29. The use of a composition comprising:

(b) a pharmaceutically effective amount of citalopram or a pharmaceutically effective salt thereof to prepare a medicament for treating or preventing diseases or disorder of the central nervous system.

30. The use according to claim 29, wherein component (a) comprises an (S,S)- enantiomer or a racemic form of reboxetine.

31. The use according to claim 29, wherein component (b) is citalopram or a hydrobromide salt thereof.

32. The use of a composition comprising:

(b) a pharmaceutically effective amount of citalopram or a pharmaceutically effective salt thereof for the manufacture of a medicament.

33. The use according to claim 32, wherein component (a) comprises an (S,S)- enantiomer or racemic form of reboxetine.

34. The use according to claim 32, wherein component (b) is citalopram or a hydrobromide salt thereof.