What is the appropriate dose of an antipsychotic in an animal model? The literature reveals no standard rationale across studies. This study was designed to use in vivo dopamine D 2 receptor occupancy as a cross-species principle for deriving clinically comparable doses for animal models. The relationship between dose, plasma levels, and in vivo dopamine D 2 receptor occupancy was established in rats for a range of doses administered as a single dose or multiple doses (daily injections or osmotic minipump infusions) for five of the most commonly used antipsychotics. As a single dose, haloperidol (0.04 -0.08 mg/kg), clozapine (5-15 mg/kg), olanzapine (1-2 mg/kg), risperidone (0.5-1 mg/kg), and quetiapine (10 -25 mg/kg) reached clinically comparable occupancies. However, when these "optimal" single doses were administered as multiple doses, either by injection or by a mini-pump, it led to no or inappropriately low trough (24-h) occupancies. This discrepancy arises because the half-life of antipsychotics in rodents is 4 to 6 times faster than in humans. Only when doses 5 times higher than the optimal single dose were administered by pump were clinically comparable occupancies obtained (e.g., haloperidol, 0.25 mg/ kg/day; olanzapine, 7.5 mg/kg/day). This could not be achieved for clozapine or quetiapine due to solubility and administration constraints. The study provides a rationale as well as clinically comparable dosing regimens for animal studies and raises questions about the inferences drawn from previous studies that have used doses unrepresentative of the clinical situation.

Conditioned avoidance response (CAR) behavior and catalepsy (CAT) are the standard preclinical tests used to predict antipsychotic activity and motor side-effect liability, respectively. Recent data in patients showUsing this technique, Farde et al. (1992) suggested that both antipsychotic response and extrapyramidal side effects (EPS) may be related to D 2 receptor occupancyalbeit with different thresholds. With typical antipsychotics, a D 2 receptor occupancy in the range of 70% was associated with clinical response while EPS emerged at a D 2 receptor occupancy Ͼ 80% (Farde et al. 1992;Nordstrom et al. 1993). This relationship has been confirmed by subsequent clinical studies. In a double-blind PET study with haloperidol, Kapur et al. found that clinical response was manifest at 65-70% D 2 receptor occupancy, but only patients with a D 2 receptor occupancy Ͼ 78% showed signs of EPS (Kapur et al. 2000a).Newly synthesized potentially antipsychotic drugs are tested in the catalepsy (CAT) test (for EPS liability) and the conditioned avoidance response (CAR) test (for

Typical antipsychotics (haloperidol) give rise to severe motor side-effects while atypical antipsychotics like clozapine do not. Action at several neurotransmitter receptors have been implicated. To identify the critical mechanisms involved we synthesized an 8-C1 isomer of clozapine which showed an equivalent affinity to clozapine on multiple receptors (5-HT1A, 5-HT2, D1, D4, M1) but differed in having a 10-fold higher affinity at the dopamine D2/3 receptor. When tested in a series of animal models indicative of the typical/atypical distinction (catalepsy, striatal gene-induction, prolactin elevation) isoclozapine lost atypical properties and behaved like a typical antipsychotic. Simultaneous in vivo receptor occupancy studies confirmed that alterations in D2 receptor occupancy were most closely related to loss of atypicality by clozapine's isomer isoclozapine. The implications for the design of future antipsychotics is discussed.

Our data suggest that these two methods are not interchangeable; the ex vivo method is much less sensitive, lacks internal consistency and hence is best avoided.

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