Varvel SA, Strong SE, Floyd CL, Haag KJ, Porter JH (1996) A comparison of olanzpine with typical and atypical antipsychotics in the paw test. (Presented at the 1996 meeting of the Eastern Psychological Association)

Schizophrenia is one of the most severe mental disorders affecting 1-2% of the population worldwide, and may represent several distinct subgroupings of related disorders. For example, one model of schizophrenia is based on a positive-negative dichotomy with positive symptoms including delusions, hallucinations (mostly acoustic), and thought disorders, and negative symptoms including flattening of affect, anhedonia, and motor retardation (Crow, Brit.J.Psychiat. 137: 383-386,1980). It is fairly well accepted that typical antipsychotic drugs (ones that produce extrapyramidal motor side effects, like chloropromazine [Thorazine] and haloperidol [Haldol] produce their therapeutic effects through blockade of dopamine receptors and there are data showing that typical antipsychotics are more effective in reducing positive symptoms than negative symptoms (see review by Ellenbroek, Pharma. Ther. 57:1-78,1993). Antipsychotic drugs that do not produce motor side effects (or greatly reduced effects) have been classified as atypical antipsychotic drugs. The most important of these is clozapine (Clozaril) which has been approve for clinical use now for several years. Not only does clozapine produce very few motor side effects, but clozapine has been shown to be at least as effective as typical antipsychotics in reducing schizophrenic symptoms and in some cases it is superior. For example, Kane et al. (Arch. Gen. Psychiat. 45:789-796,1988) have shown that clozapine is more effective than chloropromazine in patients with refractory schizophrenia, and it appears that clozapine may be more efficacious in alleviating some of the negative symptoms that are often more prevalent in patients with chronic schizophrenia.

While animal models are often used for screening purposes, currently there are no adequate preclinical screening procedures that both identify drugs as potentially useful antipsychotic agents and distinguish atypical from typical antipsychotic drugs. A preclinical test that has shown promise in this regard is the Paw Test. Ellenbroek (1993) has shown that the Paw Test distingishes atypical and typical antipsychotic drugs on the basis of forelimb(FRT) and hindlimb(HRT) retraction times when rats are placed on a platform with their legs lowered through holes. The purpose of the present study was to test the putative atypical antipsychotic drug olanzapine (Moore et al., J. Pharmacol. Exp. Ther.,262:545-551,1992) using the Paw Test procedure and to compare it to the typical antipsychotic haloperidol and the atypical antipsychotic clozapine. The antipsychotic thioridazine (Melleril) also was tested as this drug has shown properties of both atypical and typical neuroleptics in various preclinical tests.

Adult male Sprague-Dawley rats were randomly assigned to 9 Groups (N= 8/group): vehicle (VEH); 1.0 mg/kg thioridazine (THD); 20 mg/kg thioridazine; 1.0 mg/kg olanzapine (OLZ); and 3 mg/kg olanzapine (Eli Lilly). All injections were given intraperitoneally at a volume of 1 ml/kg body wieght. Following drug injections, each rat was tested at 30 min, 60 min, and 90 min in the Paw Test apparatus (a 30 x 30 cm plexiglas platform with two 4 cm holes for the forelimbs and two 5 cm holes for the hindlimbs and a slit for the tail). The rat was held gently behind the forelimbs and the hindlimbs were placed first in the holes. Then the forelimbs were lowered into the front holes. Retraction times (secs) were measured separately for both forelimb retraction time (FRT) and for hindlimb retraction time (HRT), and was defined as the time that it took the rat to withdraw at least one forelimb and one hindlimb. The minimium retraction time was defined as 1 sec and the maximium retraction time was set at 60 sec. Mann Whitney U-tests were used to compare each drug treatment to the VEH group.

Figure 1 shows the median FRT and median HRT for each of the 9 treatment conditions. Since there were no significant differences across the 3 time points the data from the 30 min, 60 min, and 90 min measurements were combined for remaining comparisions. Significant differenced from the VEH group are indicated in the figure. Haloperidol clearly had a profile that was different from clozapine, thioridazine, and olanzapine in that it was the only drug that produced an increase in FRT. The 1.0 and 2.0 mg/kg dosed of haloperidol produced significant increased in both FRT and HRT as compared to VEH; whereas clozapine, thioridazine, and olanzapine produced significant increases only in HRT. Olanzapine most closely resembled clozapine in its profile with the 3.0 mg/kg dose producing a median HRT very similar to that of the 20 mg/kg dose of clozapine.

The novel "atypical" antipsychotic compound olanzapine displayed a profile very similar to that of the atypical neuroleptic clozapine in the Paw Test. While the typical neuroleptic haloperidol produced significant increased in both FRT and HRT, the atypical neuroleptic clozapine only increased HRT. Olanzapine resembled clozapine in that only HRT was increased. Thioridazine also produced an "atypical" profile producing only increaes in HRT, although the magnitude of the effect was less for the doses that were tested.

These findings suggest that olanzapine should have an atypical profile in the clinical setting very similar to that of the atypical antipsychotic clozapine and should produce less extrapyramidal motor side effects. While a preliminary report with 10 schizophrenic partients does support this suggestion (Moore et al., Curr. Opin. Invest. Drugs, 2: 281-293, 1993), additional clinical data will be required to confirm that olanzapine displays an atypial profile in the clinical setting. We are continuing to study olanzapine in other preclinical behavioral test and comparing it to both typical and atypical neuroleptics.

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