A wide variety of models are used in the laboratory to predict whether anti-psychotics will show EPS (Table 9)^62,63.

Receptor properties of clozapine relevant to EPS
Clozapine is a multiple receptor antagonist.  It shows low to moderate affinity for the dopaminergic D₂-receptor (low potency) and high affinity for the 5HT₂ -receptor, i.e. it has a high 5HT₂:D₂ ratio.  In addition, clozapine also shows low D₂ -receptor occupancy in the basal ganglia and lack of D₂ -receptor supersensitivity following repeated dosing.  The only other drug that also shows low affinity to the D2-receptor, (compared with haloperidol, olanzapine, sertindole, ziprasidone, and risperidone) is quetiapine (ICI 204 636, also known as ‘Seroquel’).
 

Receptor binding  Catalepsy  Depolarization blockade of A9 and A10 dopamine receptors systems  Haloperidol-sensitized cebus monkey  Drug-naive cebus monkey  Drug discrimination  Regional discrimination  Regional expression of early gene products  Paw test

Table 9. Animal models used as predictors of EPS

Other atypical drugs exhibit high D₂ affinities and are therefore classified as high-potency
D2-antagonists.  In addition, clozapine, quetiapine and olanzapine can be classified as multiple receptor antagonists, whereas sertindole, ziprasidone and risperidone show a large component of 5HT2A affinity in their respective receptor binding profiles.

Catalepsy
Catalepsy  is the most commonly used test for EPS because most drugs that produce EPS in humans produce catalepsy in rodents⁶⁴. The exception to this rule is clozapine, which does not produce EPS in humans but does produce some degree of catalepsy in rodents. Comparison of effective cataleptic doses with predicted antipsychotic doses is another measure of EPS. Usually a wider separation of doses is observed with clozapine than with haloperidol.

Depolarization inactivation
This model looks at the effects of repeated antipsychotic drug treatment in the time-dependent inactivation of doparine cell firing. Clinical response to antipsychotic drugs appears to correspond to the dopamine systems affected: inhibition of dopaminergic activity in the mesolimbic and mesocortical A10 system relates to antipsychotic efficacy, whereas inhibition in the nigrostriatal A9 system relates to motor side-effects^65,66. There are, however, two limitations to the usefulness of this model. First, the regional selectivity is dose-related. Second, this phenomenon may not occur in non-anaesthetized rats.

Both clozapine and quetiapine are limbic-selective, affecting only A10 dopamine receptors, and therefore may not share the EPS liability of haloperidol ⁶⁷.  Other atypicals (olanzapine, sertindole and ziprasidone, but not risperidone) are also ‘well behaved’ on this model.

Haloperidol-sensitized Cebus Monkey
Of all the models, this is probably the most predictive of EPS in humans, as reactions in monkey are identical to EPS in man in terms of dystonia and parkinsonism⁶⁸.  Furthermore, reactions can be controlled by similar agents, such as anticholinergics and dopamine agonists.  On the basis of this model, clozapine can be unambiguously classified-it does not produce dystonia. This test therefore offers a high degree of face validity in predicting EPS in man.

The performances of the putative atypicals in this model are shown in Table 10⁶⁹. Across the dose range, clozapine does not produce any evidence of dystonic reactions, and the same conclusion can be drawn regarding quetiapine.  Both drugs exhibit low EPS across the dose range. For risperidone, the dose that produces a 100% incidence of dystonic reactions clearly lies within the antipsychotic dose range.  This correlates with clinical studies showing EPS at higher doses.  Similarly, olanzapine produces dystonic reactions with a 100% incidence at a dose of 0.5mg, which is near the top end of the antipsychotic dose range.  Surprisingly, the dose of ziprasidone that produces 100% dystonic reactions is actually below the predicted antipsychotic dose range.  Sertindole appears well behaved on this model.
 

Drug    Haloperidol   Clozapine   Quetiapine   Risperidone   Olanzapine   Sertindole   Ziprasidone

Human antipsychotic  dose range (mg po)  5–50   300–900  150–450  4–8  10–20   12–24  40–160

Predicted monkey  antipsychotic dose  range (mg/kg po)  0.1–1.0  6–18  3–9  0.08–0.16  0.02–0.4  0.24–0.48  0.8–3.2

Dose producing 100%  incidence of dystonic  reactions (mg/kg po)  0.25  >40  >40  0.125  0.5  2.5  0.62

Table 10. Dystonic reactions in haloperidol-sensitized Cebus Monkeys.

In summary, the two drugs that do not show dystonic reactions, even at doses well above the antipsychotic dose range, are clozapine and quetiapine.  This finding may be related to the fact that both of these drugs have low affinity at the D₂-receptor, where the other drugs all have high affinity (or potency) at the D₂-receptor.

Drug-naive Cebus Monkey
Chronic administration of antipsychotics to drug-naive monkeys simulates more closely the dosing conditions that produce EPS and TD in humans.  However, animal and time constraints have severely limited the utilization of this model.  Nevertheless, clozapine has been shown to lack sensitization liability.  The only two new drugs to be tested in the drug-naive monkey have been quetiapine, which has limited sensitization liability, and risperidone, which produces about the same sensitization as haloperidol⁶⁹.

Drug discrimination
This is one of the newer tests for predicting EPS.  Squirrel monkeys can be trained to discriminate between clozapine and saline injections by making a differential response on the left or right lever in an operant box, depending on whether clozapine or saline was injected⁷⁰.

Quetiapine, perlapine (a derivative of clozapine), and JL5 and JL7 (experimental dibenzodiazepines) produced dose-dependent increases in responding to the clozapine lever⁷⁰. Risperidone, remoxipride, clothiapine and loxapine failed to substitute for clozapine in this model.

Gene expression: c-Fos
The immediate early gene product c-Fos is considered to be an activity marker for some neurones.  Typical and atypical antipsychotics produce different patterns of c-Fos expression. For example, haloperidol enhances Fos-like immunoreactivity (FLI) in the medial and dorsolateral striatum, nucleus accumbens and lateral septal nucleus, whereas clozapine selectively increases FLI in limbic structures such as the nucleus accumbens, lateral septal nucleus, and prefrontal cortex⁷¹.

FosB gene expression
Another early gene product, FosB, is only expressed after chronic administration of antipsychotics, and Fos B-like immunoreactivity (FBLI) may be used to identify neurones activated by chronic antipsychotic administration⁷². Haloperidol (2 mg/kg/day) administered for 19 days has been shown to elevate FBLI in the ventral, medial and dorsolateral striatum, but not the prefrontal cortex and lateral septal nucleus. Quetiapine or clozapine (20 mg/kg/day) administered for 19 days elevates FBLI in ventral striatum, prefrontal cortex and lateral septal nucleus, but shows weak effects in the dorsolateral striatum.

Paw test
The paw test measures and compares forelimb (FRT) and hindlimb (HRT) reaction times in rats⁷³.  In this test, classical antipsychotics are equipotent in prolonging HRT and FRT, whereas atypical antipsychotics are much more potent in prolonging HRT than FRT.  Non-antipsychotic drugs, such as desipramine, diazepam, and morphine, do not influence the variables measured in the paw test.

Conclusions
The discrimination between typical and atypical antipsychotics in terms of EPS liability should be based on activity in a broad range of preclinical models, and should include cross-species comparisons.  Not all proposed atypical antipsychotics have the exact same profile as clozapine.  The results from clinical trials will help to elucidate antipsychotics with improved side-effect profiles, and perhaps help to validate (or invalidate) some of our preclinical predictors.

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