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

Description:
FIELD OF THE INVENTION 
     The present invention relates to an agent with an antidepressant activity containing 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, the (+) or (−) enantiomer thereof, the pharmacologically acceptable acid addition salts thereof and a conventional antidepressant. The combination of pramipexole and sertraline is of particular interest. 
     BACKGROUND OF THE INVENTION 
     Pramipexole—(−)-2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole—is a dopamine-D 3 /D 2  agonist, the synthesis of which is described in European Patent 186 087 and U.S. Pat. No. 4,886,812. 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 EP-A 85 116 016, and reference is hereby made specifically to the literature cited therein. 
     DESCRIPTION OF THE INVENTION 
     It has now been found that, surprisingly, pramipexole, the (+) or (−) enantiomer thereof, or the pharmacologically acceptable acid addition salts thereof, 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 by administering to rats a combination of pramipexole and sertraline and then subsequently testing them according to 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). 
     For the particular preferred combination of pramipexole and sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, their acid addition salts respectively, the test was carried out as follows. 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 sertraline or a combined dose of both antidepressants in the same therapeutic amount as the animals that received only one of the two active substances. 
     The combination of 2-amino-4,5,6,7-tetrahydro-6-n-propyl-amino-benzothiazole, the (+) or (−)-enantiomer thereof, the acceptable acid addition salts thereof and (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (sertraline) and the acid addition salts thereof is particularly preferred, while the combination of pramipexole and sertraline in the form of their hydrochlorides is most particularly preferred. 
     The invention also encompasses the combined use of pramipexole with antidepressants other than sertraline. Preferably these other antidepressants are selected from the following known compounds: alprazolam, chlordiazepoxide, clomipramine, chinpirol, dibenzepin, doxepin, fluvoxamine, lofepramine, maprotiline, mirtazapine, mianserin, moclobemide, nefazodone, nortriptyline, opipramol, paroxetine, sertraline, sulpiride, tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine and viloxazine. 
     The term “combination” for the purposes of the invention refers to either the co-administration of pramipexolc and the second antidepressant agent (with both agents being administered separately, but such that both agents will exert their therapeutic in concert) or to the administration of both agents together, as components of a single pharmaceutical dosage form. 
     Orally administered pharmaceutical formulations for pramipexole are known from the prior art and are obtainable in the German and U.S. markets. 
     The individual active substances may also be packaged in kit form as a combined pack of the individual drugs, as well as separately. 
     The combination of pramipexole and another antidepressant may be formulated analogously to conventional pharmaceutical 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, 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. 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 Alprazolam 
                 (25-100 mg) 
                 Nefazodone 
                 (100-300 mg) 
               
               
                   
               
             
             
               
                 Chlordiazepoxide 
                 (5 mg) 
                 Nortriptyline 
                 (10-25 mg) 
               
               
                 Clomipramine 
                 (10-25 mg) 
                 Opipramol 
                 (50 mg) 
               
               
                 Chinpirol 
                 (1-5 mg) 
                 Paroxetin 
                 (20 mg) 
               
               
                 Dibenzepin 
                 (10-250 mg) 
                 Sertraline 
                 (50 mg) 
               
               
                 Doxepin 
                 (5-50 mg) 
                 Sulpiride 
                 (50-200 mg) 
               
               
                 Fluvoxamine 
                 (50-100 mg) 
                 Tranylcypromine 
                 (10 mg) 
               
               
                 Lofepramine 
                 (35-75 mg) 
                 Trazodone 
                 (25-100 mg) 
               
               
                 Maprotiline 
                 (10-75 mg) 
                 Trimipramine 
                 (25-250 mg) 
               
               
                 Mianserin 
                 (10-30 mg) 
                 Tryptophan 
                 (500 mg-2.5 g) 
               
               
                 Mirtazapine 
                 (30 mg) 
                 Venlafaxine 
                 (30-75 mg) 
               
               
                 Moclobemide 
                 (150-300 mg) 
                 Viloxazine 
                 (100 mg) 
               
               
                   
               
             
          
         
       
     
     In the combination according to the invention the recommended dose may in individual cases be below the single dose previously recommended for the monopreparation. 
    
    
     DESCRIPTION OF THE EXPERIMENTS 
     Pramipexole was used in doses of 0.1 and 0.3 mg/kg. In addition, trials were carried out using 0.05 mg/kg pramipexole. Sertraline was used in doses of 5 and 10 mg/kg as mentioned in the Tables. The tests were carried out on rats (male Wistar, 250-270 g) at RT while maintaining a natural day-night rhythm. Pramipexole (HCl) was dissolved in a physiological saline solution and sertraline (HCl) was dissolved in distilled water, and both substances were injected in a volume of 2 ml/kg. 
     Forced Swimming Test in Rats 
     The total immobility time was determined according to Porsolt et al. (1978) within a five-minute observation period. Pramipexole (0.05, 0.1 and 0.3 mg/kg) and sertraline (5 or 10 mg/kg) were given three times at intervals of 24 hours, 5 hours and 1 hour before the test. 
     In separate groups pramipexole was also injected three times in the abovementioned dosage together with sertraline (5 or 10 mg/kg) as described above. Each group consisted of 10 rats. 
     Results 
     Pramipexole—0.1 mg/kg—does not alter the immobility time in the forced swimming test, whereas higher doses (0.3 mg) bring about a significant reduction in the immobility time. 
     A dosage of 5 mg/kg sertraline on its own likewise does not reduce the immobility time. However, the joint administration of 5 mg/kg of sertraline and 0.1 mg/kg of pramipexole noticeably reduces the immobility time. This effect is considerably more marked at higher doses of sertraline. 
     Sertraline alone in a dose of 10 mg/kg was inactive in the forced swimming test, but given in conjunction with pramipexole (0.1, 0.3 mg/kg). This effect is increased at higher doses of pramipexole. Pramipexole in a dosage of 0.05 mg/kg shows no effect on the immobility time but there is a reduction in the immobility time when it is combined with sertraline. 
     These results demonstrate the unexpected synergistic effect of pramipexole in conjunction with sertraline as an antidepressant. 
     
       
         
               
             
               
               
             
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Effect of pramipexole (0.1 and 0.3 mg/kg) on its own or in 
               
               
                 conjunction with sertraline (5 mg/kg) on the immobility time 
               
               
                 in the forced swimming test in rats. 
               
             
          
           
               
                 Compounds 
                 Immobility time(s) 
               
             
          
           
               
                 (mg/kg) 
                 mean ± SEM 
                 P 
               
               
                   
               
               
                 1. carrier 
                 239.9 ± 3.1 
                 — 
               
               
                 2. sertraline 5 
                 257.0 ± 7.0 
                 ns vs 1 
               
               
                 3. pramipexole 0.1 
                 223.4 ± 6.2 
                 ns vs 1 
               
               
                 4. pramipexole 0.3 
                 171.5 ± 9.2 
                 &lt;0.001 vs 1 
               
               
                 5. sertraline 5 + pramipexole 0.1 
                  96.1 ± 10.3 
                 &lt;0.001 vs 3 
               
               
                 6. sertraline 5 + pramipexole 0.3 
                  18.1 ± 3.5 
                 &lt;0.001 vs 4 
               
               
                   
               
             
          
         
       
     
     Pramipexole (0.1 or 0.3 mg/kg s.c.) and sertraline (5 mg/kg i.p.) are administered three times (24 hours, 5 hours and 1 hour) before the test. 
     
       
         
               
             
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Effect of pramipexole (0.1 and 0.3 mg/kg) on its own or in 
               
               
                 conjunction with sertraline (10 mg/kg) on the immobility time 
               
               
                 in the forced swimming test in rats. 
               
             
          
           
               
                 Compounds 
                 Immobility time(s) 
               
             
          
           
               
                 (mg/kg) 
                 mean ± SEM 
                 P 
               
               
                   
               
               
                 1. carrier 
                 237.9 ± 2.7 
                 — 
               
               
                 2. sertraline 10 
                 223.6 ± 9.9 
                 Ns vs 1 
               
               
                 3. pramipexole 0.1 
                 212.5 ± 6.9 
                 Ns vs 1 
               
               
                 4. pramipexole 0.3 
                 142.9 ± 7.9 
                 &lt;0.001 vs 1 
               
               
                 5. sertraline 10 + pramipexole 0.1 
                 133.3 ± 6.9 
                 &lt;0.001 vs 3 
               
               
                 6. sertraline 10 + pramipexole 0.3 
                  11.8 ± 2.3 
                 &lt;0.001 vs 4 
               
               
                   
               
             
          
         
       
     
     Pramipexole (0.1 or 0.3 mg/kg s.c.) and sertraline (10 mg/kg i.p.) are administered 3 times (24 hours, 5 hours and 1 hour) before the test. 
     
       
         
               
             
               
               
             
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Effect of pramipexole (0.05 mg/kg) on its own or in 
               
               
                 conjunction with sertraline (5 and 10 mg/kg) on the immobility 
               
               
                 time in the forced swimming test in rats. 
               
             
          
           
               
                 Compounds 
                 Immobility time(s) 
               
             
          
           
               
                 (mg/kg) 
                 mean ± SEM 
                 P 
               
               
                   
               
               
                 1. carrier 
                 235.3 ± 4.8 
                 — 
               
               
                 2. pramipexole 0.05 
                 245.5 ± 7.8 
                 ns vs 1 
               
               
                 3. sertraline 5 
                 247.5 ± 3.0 
                 ns vs 1 
               
               
                 4. sertraline 10 
                 223.7 ± 2.8 
                 ns vs 1 
               
               
                 5. sertraline 5 + pramipexole 0.05 
                 187.7 ± 11.2 
                 &lt;0.001 vs 2 
               
               
                 6. sertraline 10 + pramipexole 0.05 
                 163.9 ± 10.0 
                 &lt;0.001 vs 2 
               
               
                   
               
             
          
         
       
     
     Pramipexole (0.05 mg/kg s.c.) and sertraline (5 and 10 mg/kg i.p.) are administered 3 times (24 hours, 5 hours and 1 hour) before the test.