Depression is a major health problem in our society and also poses a tremendous financial burden on society due to lost self-support of persons suffering from depression. Life time prevalence for major depression is estimated to be between 5 to 10 %. Various forms of depression are distinguished which are separately diagnosed according to criteria given in handbooks for psychiatry, for example in the Diagnostic and Statistical Manual of Mental Disorders 4th edition published by the American Psychiatric Association, Washington, D. C. (1994) and in the International Classification of Diseases (ICD-10) published by the World Health Organisation (Geneva).

There is a continuous search for new methods of treatment of depression because existing methods still have disadvantages, such as the side effects of drugs, the long duration of treatments, and more importantly the partial efficacy of treatments. Treatment with existing antidepressant drugs remains without improvement in at least 30 % of patients elected for drug therapy. There is a strong need for new drugs, with other mechanisms of action than existing anti- depressants, for the treatment of depression.

Psychotropic drugs are divided in categories of therapeutic use. Anti- depressants are distinguished from other classes, such as anxiolytics and antipsychotics. Drugs in one category may have side-effects aggravating other psychiatric diseases not belonging to the category for which the drug treatment is given. Trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole is a drug known from US 4,145,434 for the treatment psychosis and anxiety.

Surprisingly, it has now been found that trans-5-chloro-2-methyl-2,3,3a, 12b- tetrahydro-1H-dibenz [2,3 : 6,7] oxepino [4,5-c] pyrrole is useful for the treatment or prophylaxis of depression.

Accordingly, the present invention provides the use of a compound of formula (A) :

Formula A which is trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3: 6, 7] oxepino [4,5-c] pyrrole, or a pharmaceutically acceptable acid addition salt or solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.

The term depression is used here for the psychiatric disorder or the symptom characterised by chronic low mood and loss of capacity to experience pleasure.

This disease or symptom is well-recognised by a physician and can also be quantified, for example with the Hamilton Rating Scale for depression or with the Montgomery and Asberg Depression Rating Scale. An important characteristic of presently and frequently diagnosed depression, for example major depression and dysthymia, is that an organic disorder causing the depression cannot be detected. A depression, due to identified pathology in the physiology or anatomy of a person is usually treated by therapeutic strategies aimed at correcting or compensating for such an organic disorder. In such a context the use of Org 5222 in medicaments for treatment of mental disorders associated with a cerebrovascular disorder is known from EP 0 730 865 A1.

Suitable acid addition salts include hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation. A preferred salt is maleic acid, in which case the compound is known as Org 5222.

The compound of formula A and its pharmaceutically acceptable acid addition salts will be referred to collectively as compounds according to the present invention.

According to a further aspect, the present invention provides a method of treating depression with a therapeutically effective amount of trans-5-chloro-2- methyl-2,3,3a, 1 2b-tetrahydro-1 H-dibenz oxepino [4,5-c] pyrrole.

The amount of a compound of the present invention, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and the condition of the person to be treated. A suitable daily dose will be in the range of 0.005 to 60 mg of a compound of the present invention per person. Preferably this dose will be in the range of from 0.03 to 2 mg. A preferred route of administration for treatment is the sublingual route. With this route, a method of providing therapy using the pharmaceutical composition of the present invention comprises the insertion of a dosage form according to this invention in the buccal pouch or under the tongue of a person.

While it is possible for a compound of the present invention to be administered alone, it is preferable to present it as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation for use in the treatment of depression comprising a compound of formula A or a pharmaceutically acceptable acid addition salt or solvate thereof, together with a pharmaceutically acceptable carrier therefor and optionally other therapeutic agents. The carrier must be"acceptable"in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof. Some examples of suitable carriers are various carbohydrates, gum acacia, calcium phosphate, gelatin, talc, magnesium stearate or mineral oil. The invention further includes a pharmaceutical formulation as herein described, in combination with packaging material adapted for the pharmaceutical formulation, said packaging material including facilities for the use of the pharmaceutical formulation in the treatment of depression. In particular, such facilities can include precautions limiting the total dose contained in the package handed over to the person for treatment in order to reduce the risk of overdosing due the misuse of the available supply.

Suitable formulations include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The sublingual route of administration is most preferred in view of the disclosure in

WO 95/23600, which is incorporated herein by reference. A dosage unit may contain between 0.005 mg and 15 mg of a compound of the present invention.

Preferably, the dosage unit contains 0.03 to 0.50 mg of Org 5222. Usually, for treatment of depression administration of 1 to 4 dosage units of the pharmaceutical formulation of the invention per day is sufficient for obtaining a therapeutic effect. The therapy may be continued for as long as necessary or desired.

The formulations may be prepared by any of the methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro <BR> <BR> et a/., Remington's Pharmaceutical Sciences (1 8'h ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and their manufacture). Such methods include the process of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients, carrying out said process by exclusion of contamination with traces of pathogens and harmful chemicals. Accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.

Formulations adapted for sublingual administration may be presented as liquid, solids or lozenges, which can comprise a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water-dispersible carrier material.

Such carrier materials are well known in the art and can be polysaccharides like hydrolyse dextran, dextrin, mannitol, and alginates, or mixtures thereof, or mixtures thereof with other carrier materials like polyvinylalcohol, polyvinylpyrrolidone and water-soluble cellulose derivatives, like hydroxypropyl cellulose. The adaptation of a formulation for sublingual administration is characterised by properties which are in favor of drug delivery within the buccal cavity and which are unfavourable for swallowing the formulation by the treated person. Such properties for a sublingual formulation may be obtained by methods available and/or known to the skilled person and comprise, for example the adjustment of the taste, the size or amount, the dosage, the surface, the viscosity and the disintegration time of the formulation. For example a small amount of a fluid formulation will be insufficient to swallow the administered dose. For a solid formulation a pleasant taste, a very small size unsuitable for swallowing, a low dose insufficient for a therapeutic effect by oral administration but sufficient for sublingual administration, a rough or sticky

surface in a moist environment, and disintegration time in a moist environment within 30 seconds or preferably 10 seconds, are all specific possibilities for implementing the adaptation for sublingual administration of the formulation. An example of a preferred carrier material for rapid disintegration of the formulation is gelatin, especially partially hydrolysed gelatin. The partially hydrolysed gelatin can be prepared be heating of a solution of gelatin in water, for example in an autoclave at about 120°C for up to 2 hours. The hydrolyse gelatin is used in concentrations of about 1 to 6 % (w/v), and preferably in concentrations of about 2 to 4 % (w/v). In general, methods for preparation of sublingual dosage forms and packages are known to the skilled person and require no further elucidation. The details of preparing specific, preferred formulations and packages can be learned from the previously incorporated WO 95/23600, and the references mentioned therein.

Formulations adapted for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as powder or granulates; as a solution or suspension. The active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.

Formulations adapted for rectal administration may be presented as a suppository or enema.

For parenteral administration, suitable formulations include aqueous and non- aqueous sterile injection. The formulations may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.

Formulation adapted for nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.

Formulations may, for example, be presented in a suitable sustained release form, for example, in a device such as the Minipump.

The compounds of the invention may be prepared by any method known in the art for the preparation of a compound of similar structure. Typically the compounds are prepared by the methods described in US 4,145,434, which is incorporated herein by reference.

The following example is for illustration and should not be considered to be limiting in anyway: Example: Differential Reinforcement of Low Rates of Responding in rats.

In the procedure of Differential Reinforcement of Low Rates of Responding (DRL 72), rats encounter a situation where lever presses in an operant chamber are rewarded with food pellets only if a delay of 72 seconds occurs between each press. In the following the term reinforcement is used instead of reward, which terms have the same meaning in the context of this specification. A response with a delay of less than 72 seconds results in the resetting of the timer to zero and no reinforcement; again 72 seconds must elapse before a response will produce reinforcement. Antidepressant-like drugs show a similar profile of action in this test: there is a decrease in overall responding, an increase in the number of food pellets earned per session and in the overall efficiency of performance (O'Donnell and Seiden J Pharmacol Exp Ther 224: 80-88; 1983).

Methods Male rats of the Long Evans strain, weighing between 300-425g, are used in these experiments. The experiments are run in standard Skinner boxes. All rats have previous training in the DRL-72 procedure. Rats are divided into separate groups and the experiment undertaken using an independent groups design.

The number of lever presses and pellets obtained in each 1 hour session are recorded and an efficiency score (pellets earned/responses) is calculated.

Statistical analysis is by one factor independent groups ANOVA, followed by post hoc Tukey HSD tests where overall significance is obtained.

Vehicle: Mulgofen (5% m/v) and NaCI (0.9% m/v) in water.

Route of administration: intraperitoneally (30 mins before session begins)

Results Experiment 1 Effect of the well-known anti-depressant drug desipramine Dose (mg/kg) Total Total N Efficiency Response Reinforcement 0 12 2.2 171.6 3.5 1.25 12 6.1 128.1** 7.4** 5 12 8.4 131.8* 9.6** 20 12 27.3** 67. 2 15.6** The numbers in the table are means of 12 rats; * = p < 0.05; ** p < 0.01; Tukey test-dose vs placebo following a significant ANOVA.

Conclusion Desipramine suppresses lever pressing in a dose-related manner and significantly increases the number of food pellets obtained and overall efficiency per session. This reflets the antidepressant effect of desipramine.

Experiment 2; Org 5222 Dose (mg/kg) Total Total N Efficiency Response Reinforcements 0 9 3.7 140.6 5 0.03 9 7.2 120.2 8.1 0.1 9 8.5 106.6 8.3 0.3 9 16.6** 97** 13. 7** The numbers in the table are means of 9 rats; * = p < 0.05; ** p < 0.01; Tukey test-dose vs placebo following a significant ANOVA.

Conclusion ORG 5222 suppresses lever pressing in a dose-related manner and significantly increased the number of pellets obtained and overall efficiency per session. This reflets the antidepressant effect of Org 5222.