Abstract:
The present invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (pramipexole), the (+)- or (−)-enantiomer thereof or one of the pharmacologically acceptable salts thereof in conjunction with another antidepressant for the improved treatment of depression and depressive states.

Description:
RELATED APPLICATIONS 
     This application is a continuation of International Application PCT/EP98/04691, filed on Jul. 27, 1998. Benefit of the filing date of the prior International Application is hereby claimed, pursuant to 35 U.S. C. §§365(c) and 120. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to an agent with an antidepressant activity containing 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole or the (+) or (−)enantiomer thereof, the pharmacologically acceptable acid addition salts thereof and a conventional antidepressant. 
     PRIOR ART 
     Pramipexole-2-amino-6-n-propylamino4,5,6,7-tetrahydrobenzo-thiazole-dihydrochloride—is a dopamine-D 3 /D 2  agonist, the synthesis of which is described in European Patent 186 087. Pramipexole is known primarily for treating schizophrenia and particularly for the treatment of Parkinson&#39;s disease. German Patent Application DE 38 43 227 discloses that pramipexole lowers the prolactin serum level, and it is also known from German Patent Application DE 39 33 738 to use pramipexole to lower high TSH levels. Its transdermal administration is disclosed in U.S. Pat. No. 5,112,842, and WO Patent Application PCT/EP93/03389 describes the use of pramipexole as an antidepressant. 
     Details of the preparation of the title compound can be found in EPO/86 087A1, and reference is hereby made specifically to the literature cited therein. 
    
    
     DESCRIPTION OF THE INVENTION 
     It has now been found that, surprisingly, pramipexole combined with another antidepressant has a significantly greater antidepressant activity than either of the two individual components taken alone. The fact that the combination of active substances takes effect immediately should be particularly emphasised. 
     The improvement in the effect of pramipexole by the simultaneous administration of another antidepressant was discovered in tests on rats using the so-called “forced swimming test”. Details of this test method can be found, for example, in Willner, Psychopharmacology 83, 1-16 (1984) or Borsini and Meli, Psychopharmacology 94, 147-160 (1988). 
     The test can be carried out as follows for each of the combinations of active substances tested. The animals were divided up into different groups and each group was given either a saline solution, a therapeutically effective amount of pramipexole, a therapeutic amount of a second antidepressant other than pramipexole or a combined dose of pramipexole and the other antidepressant in the same therapeutic amount as the animals that received only one of the two active substances. 
     A selection of the results of the tests is shown in Table 1: 
     
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Combination of active 
                 Groups 
                 Immobility 
               
               
                 substances 
                 (active substance in mg/kg) 
                 time(s) 
               
               
                   
               
             
             
               
                 Pramipexole + imipramine 
                 Common salt 
                  207.4 ± 10.2 
               
               
                   
                 Pramipexole 
                 129.4 ± 8.1 
               
               
                   
                 Imipramine 
                  147.3 ± 10.5 
               
               
                   
                 Pramipexole + imipramine 
                  40.8 ± 9.7 
               
               
                 Pramipexole + amitriptyline 
                 Common salt 
                 231.3 ± 8.2 
               
               
                   
                 Pramipexole 
                 164.3 ± 9.8 
               
               
                   
                 Amitriptyline 
                 174.6 ± 9.2 
               
               
                   
                 Pramipexole + amitriptyline 
                  55.6 ± 8.7 
               
               
                 Pramipexole + citalopram 
                 Common salt* 
                 231.3 ± 8.2 
               
               
                   
                 Pramipexole* 
                 164.3 ± 9.8 
               
               
                   
                 Citalopram 
                 233.5 ± 9.8 
               
               
                   
                 Pramipexole + citalopram 
                  82.1 ± 11.2 
               
               
                 Pramipexole + fluoxetin 
                 Common salt 
                 221.4 ± 4.9 
               
               
                   
                 Pramipexole 
                  131.0 ± 10.0 
               
               
                   
                 Fluoxetin 
                 236.9 ± 7.4 
               
               
                   
                 Pramipexole + fluoxetin 
                  80.2 ± 10.7 
               
               
                   
               
               
                 *Group is identical to group from the series Pramipexole plus amitriptyline  
               
             
          
         
       
     
     The results described above demonstrate the clearly improved effect of the combined administration of pramipexole and another antidepressant compared with the administration of the individual substances. 
     Other embodiments relate to the combined administration of pramipexole with one of the following antidepressants: 
     
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 alprazolam 
                 fluoxetin 
                 opipramol 
               
               
                   
                 amitriptyline 
                 fluvoxamine 
                 paroxetine 
               
               
                   
                 amitriptyline oxide 
                 imipramine 
                 sertraline 
               
               
                   
                 chlordiazepoxide 
                 lofepramine 
                 sulpiride 
               
               
                   
                 citalopram 
                 maprotiline 
                 tranylcypromine 
               
               
                   
                 clomipramine 
                 mianserin 
                 trazodone 
               
               
                   
                 chinpirol 
                 mirtazapine 
                 trimipramine 
               
               
                   
                 dibenzepin 
                 moclobemide 
                 tryptophan 
               
               
                   
                 doxepin 
                 Nefazodone 
                 venlafaxine or 
               
               
                   
                   
                 Nortriptyline 
                 viloxazine 
               
               
                   
                   
               
             
          
         
       
     
     The combination of pramipexole and another antidepressant may be formulated analogously to conventional galenic preparations, generally together with a pharmaceutical carrier. In other words an effective dose of the individual components and optionally a pharmaceutical carrier are formulated as plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories etc. For pramipexole the pharmaceutically effective dose per patient is between 0.01 and 10 mg, preferably between 0.08 and 5 mg. 
     The therapeutically effective doses of the second antidepressant in the combination are given in the Table which follows. 
     
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 (25-100 mg) 
                 alprazolam, 
               
               
                   
                 (10-50 mg) 
                 Amitriptyline, 
               
               
                   
                 (30-120 mg) 
                 Amitriptyline oxide 
               
               
                   
                 (5 mg) 
                 chlordiazepoxide, 
               
               
                   
                 (20-40 mg) 
                 Citalopram, 
               
               
                   
                 (10-25 mg) 
                 Clomipramine, 
               
               
                   
                 (1-5 mg) 
                 chinpirol, 
               
               
                   
                 (10-250 mg) 
                 Dibenzepin, 
               
               
                   
                 (5-50 mg) 
                 doxepin, 
               
               
                   
                 (10-30 mg) 
                 Fluoxetin, 
               
               
                   
                 (50-100 mg) 
                 fluvoxamine, 
               
               
                   
                 (10-25 mg) 
                 lmipramine, 
               
               
                   
                 (35-75 mg) 
                 lofepramine, 
               
               
                   
                 (10-75 mg) 
                 maprotiline, 
               
               
                   
                 (10-30 mg) 
                 mianserin, 
               
               
                   
                 (30 mg) 
                 Mirtazapine, 
               
               
                   
                 (150-300 mg) 
                 Moclobemide, 
               
               
                   
                 (100-300 mg) 
                 Nefazodone, 
               
               
                   
                 (10-25 mg) 
                 Nortriptyline, 
               
               
                   
                 (50 mg) 
                 Opipramol, 
               
               
                   
                 (20 mg) 
                 Paroxetin, 
               
               
                   
                 (50 mg) 
                 Sertraline, 
               
               
                   
                 (50-200 mg) 
                 Sulpiride, 
               
               
                   
                 (10 mg) 
                 Tranylcypromine, 
               
               
                   
                 (25-100 mg) 
                 Trazodone, 
               
               
                   
                 (25-250 mg) 
                 Trimipramine, 
               
               
                   
                 (500 mg-2.5 g) 
                 Tryptophan, 
               
               
                   
                 (30-75 mg) 
                 Venlafaxine or 
               
               
                   
                 (100 mg) 
                 Viloxazine. 
               
               
                   
                   
               
             
          
         
       
     
     In the combination according to the invention the recommended dose may in individual cases be below the single dose previously recommended for the monopreparation. 
     The term combination for the purposes of the invention refers to an active substance combination of the two active substances in a formulation and also as a combination in the sense of individual formulations of the active substances administered at specified intervals from one another in a therapeutic treatment. Orally administered pharmaceutical formulations for pramipexole are known from the prior art and are obtainable under the brand name Sifrol. 
     The individual active substances may also be packaged in kit form as a combined pack of the individual drugs, as well as separately.