AU734011B2 - Method for treating bipolar disorder - Google Patents

Description

WO 97/33577 PCTIS96/19575 -1- METHOD FOR TREATING BIPOLAR DISORDER This invention provides a method for using 2methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine, (hereinafter referred as "olanzapine"), for the treatment of bipolar disorder.

Bipolar Disorder is a psychiatric condition which is prevelant across cultures and age groups. The lifetime prevalence of Bipolar Disorder can be as high as DSM- IY, p. 353 (American Psychiatric Association, Washington, D.C. 1994). Bipolar Disorder is a recurrent disorder characterized by one or more Manic Episodes immediately before or after a Major Depressive Episode or may be characterized by one or more Major Depressive Episodes accompanied by at least one Hypomanic Episode. Additionally, the symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. In some cases the Hypomanic Episodes themselves do not cause impairment; however, the impairment may result from the Major Depressive Episodes or from a chronic pattern of unpredictable mood episodes and fluctuating unreliable interpersonal and occupational functioning. The symptoms of Bipolar Disorder must not be better accounted for by a psychotic condition or due to the direct physiological effects of a medication, other somatic treatments for depression, drugs of abuse, or toxin exposure.

Bipolar Disorder is associated with a significant risk of completed suicide. Further, the patient suffering from Bipolar Disorder is likely to suffer from school truancy, school failure, occupational failure, or divorce.

Therefore, Bipolar Disorder is a serious, fairly prevelant, psychological condition which is clearly distinguished from psychotic conditions such as schizophrenia. DSM-IV, p. 353 (American Psychiatric Association, Washington, D.C. 1994). DSMI-IV, p. 353 (American Psychiatric Association, Washington, D.C. 1994).

It is known that olanzapine can provide antipsychotic activity and is currently undergoing investigation for this purpose. Olanzapine is a known compound and described in U.S. Patent No. 5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis. U.S. Patent No. 5,229,382 is herein incorporated by reference in its entirety. However, olanzapine v'as not known to be useful for the treatment of Bipolar Disorder. Applicants have discovered that olanzapine can be useful for the treatment of bipolar disorder. Olanzapine 1i could address a long felt need for treatments which provide a favourable safety profile and effectively provide relief for the patient suffering from Bipolar Disorder.

Further, olanzapine can be useful for treating Bipolar Disorder, Major Depressive Episode. Thus, olanzapine can be a useful treatment for Bipolar Disorder wherein the Bipolar Disorder is not characterised by a manic episode.

i The aim of the invention is to overcome at least one of the prior art disadvantages.

According to a first embodiment of the present invention there is provided a method for treating bipolar disorder comprising administering to a mammal in need of such treatment, from about Img to abut 25mg per day of olanzapine, or a pharmaceutically acceptable salt thereof.

According to a second embodiment of the present invention there is provided olanzapine, from about Img to about 25mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder in a mammal in need of such treatment.

*According to a third embodiment of the present invention there is provided use of from about Img to about 25mg per day of olanzapine, or a pharmaceutically acceptable 25 salt thereof in the manufacture of a medicament for treating bipolar disorder in a mammal S. in need of such treatment.

According to a fourth embodiment of the present invention there is provided a method for treating bipolar disorder, wherein the patient suffering from or susceptible to bipolar disorder does not experience mania, comprising administering from about to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof to a patient in need thereof.

According to a fifth embodiment of the present invention there is provided olanzapine, from about 2.5mg to about 3 0mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder in a patient in need of such treatment IR:\I.IBVV]02294speci.doc:njc 3 wherein the patient suffering from or susceptible to bipolar disorder does not experience mania.

According to a sixth embodiment of the present invention there is provided use of from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder in a patient in need of such treatment wherein the patient suffering from or susceptible to bipolar disorder does not experience mania.

According to a seventh embodiment the present invention there is provided a method for treating bipolar disorder, major depressive episode, comprising administering from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof to a patient in need thereof.

According to an eighth embodiment the present invention there is provided olanzapine, from about 2.5mg to about 30mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder, major depressive episode in a patient in need thereof.

According to a ninth embodiment the present invention there is provided use of from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder, major depressive episode in a patient in need thereof.

S 20 Olanzapine is of the formula

NCH

3 N S-

(I

H Sor an acid addition salt thereof.

SGenerally, Bipolar Disorder involves at least one manic episode; however, some patients suffering from Bipolar Disorder experience Major Depressive episodes. The present invention provides a method for treating the patient suffering from or susceptible to Bipolar Disorder, wherein the patient fails to experience a manic episode.

R:\LI BVV]02324speci.doc:njc It is especially preferred that olanzapine will be the Form 11 olanzapine polymnorph having a typical x-ray powder diffraction pattern as represented by the following interplanar spacings: d 10.2689 8.577 7.4721 7.125 6. 1459 6.071 5.4849 5.2181 5.1251 4.9874 *010 a .00.

I R:\L113\VjO2294speci.doomjc WO 97/33577 PCT/US96/19575 -4- 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 A typical example of an x-ray diffraction pattern for Form II is as follows wherein d represents the interplanar spacing and I/I represents the typical relative intensities: d I/Il 10.2689 100.00 8.577 7.96 7.4721 1.41 7.125 6.50 6.1459 3.12 6.071 5.12 5.4849 0.52 5.2181 6.86 5.1251 2.47 WO 97/33577 PCT/US96/19575 4.9874 7.41 4.7665 4.03 4.7158 6.80 4.4787 14.72 4.3307 1.48 4.2294 23.19 4.141 11.28 3.9873 9.01 3.7206 14.04 3.5645 2.27 3.5366 4.85 3.3828 3.47 3.2516 1.25 3.134 0.81 3.0848 0.45 3.0638 1.34 3.0111 3.51 2.8739 0.79 2.8102 1.47 2.7217 0.20 2.6432 1.26 2.6007 0.77 The x-ray diffraction patterns set out herein were obtained using a Siemens D5000 x-ray powder diffractometer having a copper Ka radiation source of wavelength, X=1-541A.

It is further preferred that the Form II olanzapine polymorph will be administered as the substantially pure Form II olanzapine polymorph.

As used herein "substantially pure" refers to Form II associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I. Further, "substantially pure" Form II will contain less than about 0.5% related substances, wherein "related substances" refers to undesired chemical impurities or residual solvent or water.

WO 97/33577 PCT/US96/19575 -6- The polymorph obtainable by the process taught in the '382 patent will be designated as Form I and has a typical x-ray powder diffraction pattern substantially as follows, obtained using a Siemens D5000 x-ray powder diffractometer, wherein d represents the interplanar spacing: d 9.9463 8.5579 8.2445 6.8862 6.3787 6.2439 5.5895 5.3055 4.9815 4.8333 4.7255 4.6286 4.533 4.4624 4.2915 4.2346 4.0855 3.8254 3.7489 3.6983 3.5817 3.5064 3.3392 3.2806 3.2138 3.1118 3.0507 2.948 2.8172 2.7589 WO 97/33577 PCT/US96/19575 -7- 2.6597 2.6336 2.5956 A typical example of an x-ray diffraction pattern for Form I is as follows wherein d represents the interplanar spacing and I/Ii represents the typical relative intensities: d I/I1 9.9463 100.00 8.5579 15.18 8.2445 1.96 6.8862 14.73 6.3787 4.25 6.2439 5.21 5.5895 1.10 5.3055 0.95 4.9815 6.14 4.8333 68.37 4.7255 21.88 4.6286 3.82 4.533 17.83 4.4624 5.02 4.2915 9.19 4.2346 18.88 4.0855 17.29 3.8254 6.49 3.7489 10.64 3.6983 14.65 3.5817 3.04 3.5064 9.23 3.3392 4.67 3.2806 1.96 3.2138 2.52 3.1118 4.81 3.0507 1.96 2.948 2.40 WO 97/33577 PCT/US96/19575 -8- 2.8172 2.89 2.7589 2.27 2.6597 1.86 2.6336 1.10 2.5956 1.73 The x-ray powder diffraction patterns herein were obtained with a copper Kaof wavelengthX 1.541A. The interplanar spacings in the column marked are in Angstroms. The typical relative intensities are in the column marked "I/I1".

As used herein, the term "mammal" shall refer to the Mammalia class of higher vertebrates. The term "mammal" includes, but is not limited to, a human. The term "treating" as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.

As used herein, the term "Bipolar Disorder" shall refer to a condition characterized as a Bipolar Disorder, in the DSM-IV-R. Diagnostic and Statistical Manual of Mental Disorders. Revised, 3rd Ed. (1994) as catagory 296.xx. To further clarify, Applicants contemplate the treatment of both Bipolar Disorder I and Bipolar disorder II as described in the DSM-IV-R. The DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic catagories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress.

The results of pharmacological studies show that olanzapine has muscarinic cholinergic receptor activity. The compound is active at the dopamine D-l and D-2 receptors as indicated by an IC50 of less than 1 uM in the 3H-SCH233390 (Billard, et al. Life Sciences 35:1885 (1984)) and the 3H spiperone (Seeman et al Nature 216:717 (1976)) binding assays WO 97/33577 PCTIUS96/19575 -9respectively. Further, olanzapine is active at the 5-HT-2 receptor and 5-HT1C receptor. The complex pharmacological profile of the compound provides a medicament which can be useful for the treatment of Bipolar Disorder.

The usefulness of the compound for treating a Bipolar Disorder can be supported by the following studies as described.

I.

Clinical observations.

A double-blind multicenter clinical trial was designed to assess the safety and efficacy of olanzapine.

Patients were randomized to olanzapine or placebo. The results of the study suggest that olanzapine can be useful for the treatment of Bipolar Disorder.

Olanzapine is effective over a wide dosage range, the actual-dose administered being dependent on the condition being treated. For example, in the treatment of adult humans, dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be used. A once a day dosage is normally sufficient, although divided doses may be administered.

For treatment of a Bipolar Disorder, a dose range of from 1 to 30 mg, preferably 1 to 20 mg per day is suitable.

Radiolabelled olanzapine, can be detected in the saliva and thus the compound can potentially be monitored in patients to assess compliance.

A preferred formulation of the invention is a solid oral formulation comprising from about 1 to about mg or 1 to 10 mg of olanzapine as an effective amount of the active ingredient.

Most preferably, the solid oral formulation is contained in packaging materials which protect the formulation from moisture and light. For example, suitable packaging materials include amber colored high density polyethylene bottles, amber colored glass bottles, and other containers made of a material which inhibits the passage of light. Most preferably, the packaging will include a desiccant pack. The container may be sealed with an aluminum foil blister to provide the desired protection and maintain product stability.

Olanzapine will normally be administered orally or by injection and, for this purpose, it is usually employed in the form of a pharmaceutical composition.

Accordingly, pharmaceutical compositions comprising olanzapine, as active ingredient associated with a pharmaceutically acceptable carrier may be prepared. In making the compositions of the invention conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. The active ingredient can be absorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are lactose, dextrose, 1: 5 sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, i gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxy-benzoate, talc, magnesium S stearate or mineral oil. The compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

20 Depending on the method of administration, the compositions for the treatment of central nervous system conditions in general, and bipolar disorder in particular, may be formulated as tablets, capsules, injection solutions for parenteral use, gel or suspension for transdermal delivery, suspensions or elixirs for oral use or suppositories. Preferably the compositions are formulated in a unit dosage form, each dosage containing from 0.25 to 25mg, more usually 1 to 20mg, of the active (RA\LIBAA]08097doe:kww WO 97/33577 PCT/US96/19575 -11ingredient. An alternative preferred composition is a unit dosage form containing from 1 to 30 mg.

The materials for the present invention can be purchased or prepared by a variety of procedures well known to those of ordinary skill in the art. Olanzapine can be prepared as described by Chakrabarti in U.S. Patent No 5,229,382 herein incorporated by reference in its entirety. Further, the following preparations illustrate a method for preparing of the especially preferred Form II olanzapine polymorph.

Compound characterization methods include, for example, x-ray powder pattern analysis, thermogravimetric analysis (TGA), differential scanning calorimetery (DSC), titrametric analysis for water, and H-NMR analysis for solvent content.

The following examples are provided for purposes of illustration and are not to be construed as limiting the scope of the claimed invention.

Preparation 1 Technical Grade olanzapine

NH

2

N-

N

S, N.HCI S HN N \N H Intermediate 1 In a suitable three neck flask the following was added: Dimethylsulfoxide (analytical): 6 volumes Intermediate 1 75 g WO 97/33577 PCT/US96/19575 -12- N-Methylpiperazine (reagent) 6 equivalents Intermediate 1 can be prepared using methods known to the skilled artisan. For example, the preparation of the Intermediate 1 is taught in the '382 patent.

A sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction. The reaction was heated to 120 0 C and maintained at that temperature throughout the duration of the reaction. The reactions were followed by HPLC until 5 5% of the intermediate 1 was left unreacted.

After the reaction was complete, the mixture was allowed to cool slowly to 20 0 C (about 2 hours). The reaction mixture was then transferred to an appropriate three neck round bottom flask and water bath. To this solution with agitation was added 10 volumes reagent grade methanol and the reaction was stirred at 20 0 C for 30 minutes. Three volumes of water was added slowly over about 30 minutes. The reaction slurry was cooled to zero to 5°C and stirred for 30 minutes. The product was filtered and the wet cake was washed with chilled methanol. The wet cake was dried in vacuo at 45°C overnight.

The product was identified as technical olanzapine.

Yield: 76.7%; Potency: 98.1% Preparation 2 Form II olanzapine polymorph A 270 g sample of technical grade 2-methyl-4-(4methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in anhydrous ethyl acetate (2.7 L) The mixture was heated to 76 0 C and maintained at 76 0 C for minutes. The mixture was allowed to cool to 25 0 C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using x-ray powder analysis.

Yield: 197 g.

WO 97/33577 PCT/US96/19575 -13- The process described above for preparing Form II provides a pharmaceutically elegant product having potency 97%, total related substances 0.5% and an isolated yield of 73%.

EXAMPLE 1 A portion.of the hydroxypropyl cellulose was dissolved in purified water to form a solution for granulation. The remaining hydroxypropyl cellulose (total of 4.0% w/w final tablet weight), which was an extra fine grade, was combined with the olanzapine (1.18% lactose (79.32% w/w) and a portion of the crospovidone w/w) in a high shear granulator. All ingredients were security sieved prior to addition and dry blended in the granulator. This mixture was then granulated with the hydroxypropyl cellulose solution in the high shear granulator. The granulation was wet sized using standard methods. The wet granulation was then dried in a fluidized bed dryer and sized. The material was then added to a tumble bin mixer.

The running powders consisting of microcrystalline cellulose (granular) (10% magnesium stearate and the remainder of the crospovidone were added to the sized granulation. The mixture was blended and compressed with the appropriate tooling on tablet compression equipment.

Subcoatina: Hydroxypropyl methylcellulose (10% w/w) was mixed with purified water to form a solution. Core tablets were divided into approximately equal sections and spray coated with the hydroxypropyl methylcellulose solution The operation was performed in a perforated coating pan.

WO 97/33577 PCTIUS96/19575 -14- Coatina of Core Tablets: Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide) was mixed with purified water to form the coating suspension.

Subcoated tablets were divided into approximately equal sections and spray coated with the coating suspension described above. The operation was performed in a perforated coating pan.

The coated tablets were lightly dusted with carnauba wax and imprinted with appropriate identification.

Claims (3)

1. 4. A method of any one of claims 1 to 3 whierein the olanzapine is Form I1 olanzapine polyi-orphi having a typical x-ray diffraction pattern ais f'ollo\.vs, wvherein d rep~resents the interlplanar slpacInI0 I d
2. 10.2689 8.577 7 .472 1 7.125
3. 156.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.715 8 S. 4.4787 4.3307 a 4.2294 4.141 3 .9873 3 .7206 3 .5645 315366 3 .3828 3 .25 16 3.134 3 .0848 3.0638 R:AL 11 I 3 \V\0 22 94speci~doc 16 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 A method of claim 4 wherein the amount of olanzapine is lfrom about Img to 1about 20mg per day. 6. The method of any one of claims I to 5 wherein said mammal is a human. 11 7. Olanzapine, from about Img to about 25mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder in a minammal in need of such treatment. Olanzapine of claim 7 wherein the bipolar disorder is bipolar disorder 1. R. Olanzapine of claim 7 wherein the bipolar disorder is bipolar disorder 11. i 10. Olanzapine of any one of claims 7 to 9 wherein the olanzapine is Form 11 olanzapine polymorph having a typical x-ray diffraction pattern as follows, wherein d represents the interplanar spacing: d 10.2689 0 8.577 7.4721 7.125 6.1459 6.071 155.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 T 5 3.9873 R:\I.B\'1V\02294speci.doc 17 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 I Olanzapine of claim 10 wherein the amount of olanzapine is from about I mg to about 2 0mg per day. 12. Olanzapine of any one of claims 7 to 11 wherein said mammal is a human. 13. Use of from about Img to about 25mg per day of olanzapine, or a pharmaceutically acceptable salt'thereof in the manufacture of a medicament for treating 2o bipolar disorder in a mammal in need of such treatment. 14. A use of claim 13 wherein the bipolar disorder is bipolar disorder I. 15. A use of claim 13 wherein the bipolar disorder is bipolar disorder II. 16. A use of any one of claims 13 to 15 wherein the olanzapine is Form II olanzapine polymorph having a typical x-ray diffraction pattern as follows, wherein d represents the interplanar spacing: d 10.2689 8.577 7.4721 :0 7.125 6.1459 6.071 5.4849 sr 55.2181 5.1251 I A VV\02294speci. doc o 18 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 17. A use of claim 14 wherein the amount of olanzapine is from about Img to about 20mg per day. 1 8. The use of any one of claims 13 to 17 wherein said mammal is a human. 19. A method for treating bipolar disorder, wherein the patient suffering from o- susceptible to bipolar disorder does not experience mania, comprising administering from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof to a patient in need thereof. A method of claim 19 wherein olanzapine is Form II. 21. The method of claim 19 or 20 wherein the patient is a human. 22. Olanzapine, from about 2.5mg to about 30mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder in a patient in need of such treatment wherein the patient suffering from or susceptible to bipolar disorder does not experience mania. R:\LIB\'V\02294speci.doc 19 23. Olanzapine of claim 22 wherein olanzapine is Form II. 24. Olanzapine of claim 22 or 23 wherein said patient is a human. Use of from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder in a patient in need of such treatment wherein the patient suffering from or susceptible to bipolar disorder does not experience mania. 26. A use of claim 25 wherein olanzapine is Form II. 27. The use of claim 25 or 26 wherein said patient is a human. 28. A method for treating bipolar disorder, major depressive episode, comprising I0 administering from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof to a patient in need thereof. 29. The method of claim 28 wherein said patient is a human. Olanzapine, from about 2.5mg to about 30mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder, major depressive episode in a patient in need thereof. 31. Olanzapine of claim 30 wherein said patient is a human. 32. Use of from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder, major depressive episode in a patient in need thereof. 20 33. The use of claim 32 wherein said patient is a human. S* 34. A method of treating bipolar disorder comprising administering to a mammal in need of such treatment, from about Img to about 25mg per day of olanzapine, or a pharmaceutically acceptable salt thereof, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. 35. Olanzapine, from about Img to about 25mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder in a mammal in need of such treatment, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. 36. Use of from about 1mg to about 25mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder in a mammal in need of such treatment, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with i reference to Preparation 1 or 2 or Example 1. R:\LIBVV\02323speci.doc 37. A method for treating bipolar disorder, wherein the patient suffering from or susceptible to bipolar disorder does not experience mania, comprising administering from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof to a patient in need thereof, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. 38. Olanzapine, from about 2.5mg to about 30mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder in a patient in need of such treatment wherein the patient suffering from or susceptible to bipolar disorder does not experience mania, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. 39. Use of from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder in a patient in need of such treatment wherein the patient suffering from or susceptible to bipolar disorder does not experience mania, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. 40. A method for treating bipolar disorder, major depressive episode, comprising administering from about 2.5mg to about 30mg per day of olanzapine, or a 20 pharmaceutically acceptable salt thereof to a patient in need thereof, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. 41. Olanzapine, from about 2.5mg to about 30mg per day, or a pharmaceutically acceptable salt thereof when used to treat bipolar disorder, major depressive episode in a 25 patient in need thereof, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. R:\L.IBVV\02323spcci.doc 21 42. Use of from about 2.5mg to about 30mg per day of olanzapine, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating bipolar disorder, major depressive episode in a patient in need thereof, which olanzapine or pharmaceutically acceptable salt thereof is substantially as herein described with reference to Preparation 1 or 2 or Example 1. Dated 27 March, 2001 Eli Lilly and Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON o•* R :\LI1VV\02323spcci doc