Method for treating depression with olanzapine

This invention relates to the use of the antipsychotic drug olanzapine for the treatment of depression, including depressive signs and symptoms and Major Depression.

This invention relates to a method for treating depression using 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
Major Depressive Disorder is associated with a high mortality. Up to 15% of 
individuals with severe Major Depressive Disorder die by suicide. 
Epidemiological evidence also suggests that there is a fourfold increase 
in death rates in individuals with Major Depressive Disorder who are over 
age 55 years. Individuals admitted to nursing homes with Major Depressive 
Disorder have a markedly increased likelihood of death in the first year. 
Depression is a prevalent condition. The lifetime risk for Major Depressive 
Disorder in community samples has varied from 10% to 25% for women and 5% 
to 12% for men. The prevalence of Major Depressive Disorder appear to be 
unrelated to ethnicity, education, income, or marital status. 
The 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine c 
ompound is described in U.S. Pat. No. 5,229,382 ('382), herein incorporated 
by reference in its entirety. 
The presently claimed invention provides a method for treating depressive 
signs and symptoms comprising administering an effective amount of a 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
compound to a patient in need thereof. 
Additionally, the present invention provides a method for treating major 
depression comprising administering an effective amount of a 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
compound to a patient in need thereof. 
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine, 
is a compound of Formula(I): 
##STR1## 
and is described in the '382 patent. The '382 patent teaches that 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
can be useful for the treatment of psychotic conditions and mild anxiety 
states. 
Surprisingly, and in accordance with the present invention, Applicants have 
discovered that 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
can be useful for treating depressive signs and symptoms. 
The usefulness of 
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
for treating depressive signs and symptoms can be demonstrated by clinical 
trial. 
Such effectiveness for the treatment, amelioration and/or prevention of 
depressive signs and symptoms was shown in the following clinical trial: 
The study was an international double-blind, parallel trial conducted in 
one thousand nine hundred ninety six (1,996) subjects. Individuals were 
randomized 2:1 to either 
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
or haloperidol (5 to 20 mg per day) for six weeks. Subjects were evaluated 
weekly using the MADRS standardized assessment tool. Depressive signs and 
symptoms were related to suicidality. 
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was statistically significantly better than haloperidol in baseline 
endpoint MADRS total score change. A statistically significant number of 
subjects in the haloperidol treatment group demonstrated a worsening of 
depressive signs and symptoms. 
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 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 1 to 40 mg, and most preferably 5 to 
30 mg per day may be used. A once a day dosage is normally sufficient, 
although divided doses may be administered. For treatment of depressive 
signs and symptoms in a human, a dose range of from about 2.5 to 30 mg, 
preferably 5 to 25 mg per day is suitable. Radiolabelled 
2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine, 
can be detected in the saliva and thus the compound can potentially be 
monitored in patients to assess compliance. 
The 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine c 
ompound will normally be administered orally for the treatment of 
depressive signs and symptoms, or may be administered by injection and, 
for this purpose, it is usually employed in the form of a pharmaceutical 
composition. Other suitable formulations are taught in the '382 patent. 
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. 
For the treatment of depressive signs and symptoms, the patient may be a 
non-human mammal. In such instances, the 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
compound may be administered as a feed additive, tablet, or transdermally. 
Methods for preparing 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
are provided by the '382 patent; however, the following examples may be 
instructive as well.

EXAMPLE 1 
Technical Grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
##STR2## 
In a suitable three neck flask the following was added: 
Dimethylsulfoxide (analytical): 6 volumes 
Intermediate 1: 75 g 
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.degree. C. and 
maintained throughout the duration of the reaction. The reactions were 
followed by HPLC until .ltoreq.5% of the intermediate 1 was left 
unreacted. After the reaction was complete, the mixture was allowed to 
cool slowly to 20.degree. C. (about 2 hours). Each 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.degree. C. for 30 minutes. 
Three volumes of water was added slowly over about 30 minutes. The 
reaction slurry was cooled to zero to 5.degree. 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.degree. C. overnight. The 
product was identified as technical 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
Yield: 76.7%; Potency: 98.1% The procedure of Example 1 was repeated 
substantially as described above and provided a yield of 81% with a 
potency of 101.1%. 
EXAMPLE 2 
Technical Grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
Intermediate 1 (supra) was suspended in DMSO (3.2 vol.) and toluene (4.5 
vol.). A portion (.apprxeq.0.65 vol.) of the solvent was removed by 
distillation at 120-125.degree. C. The mixture was cooled to 110.degree. 
C., N-methylpiperazine(NMP, 4.2 equiv.) was added and the mixture heated 
back to reflux (120-125.degree. C.). Another portion (.apprxeq.1 vol.) of 
the solvent was removed by distillation to dry the reaction mixture. A 
vigorous reflux was desired to drive the reaction to completion (about 7 
hrs.) by removing ammonia from the reaction. The product was isolated by 
the slow addition of water (12.75 vol.) to the cooled (10.degree. C.) 
reaction solution. The product was collected by filtration and washed with 
chilled water (2 vol.). The crude 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was dried in vacuo at 60.degree. C. The product was recrystallized from 
hot toluene (5 vol.) to give a technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
After drying in vacuo at 50.degree. C., the technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was recrystallized again from ethyl acetate (10 vol.)/toluene (0.62 
vol.)/methanol (3.1 vol.) to give 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
as a methanol solvate. The methanol solvate upon drying at &gt;50.degree. C. 
was converted to an anhydrous technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
EXAMPLE 3 
Tablet Formulation 
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 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
compound (1.18% w/w), lactose (79.32% w/w) and a portion of the 
crospovidone (5% 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 outside powders consisting of microcrystalline cellulose (granular) 
(10% w/w), magnesium stearate (0.5% w/w), 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. 
Subcoating: 
Hydroxypropyl methylcellulose (1.5% 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. 
Coating 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.