Antipsychotic Dosing in Preclinical Models Is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy

Abstract

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.

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

“…We believe a higher dose of haloperidol would not have been any more effective as a dose of 0.075 mg/kg haloperidol was less efficacious to reverse the amphetamine deficit in reversal learning when compared to the dose of 0.05 mg/kg [28] and a dose of 0.1 mg/kg was shown to impair performance [1]. Furthermore 0.05 mg/kg haloperidol has been shown to occupy 50% of dopamine D 2 receptors [34,35].…”

“…Clozapine has a lower affinity for D 2 receptors than risperidone [4]. It is believed that a 40-80% threshold of D 2 receptor occupancy is required to achieve an antipsychotic response [35]. Clozapine is able to reach its antipsychotic response at 45-65% D 2 receptor occupancy levels [35].…”

“…Furthermore, this dose of haloperidol has been shown to occupy 50% of dopamine D 2 receptors [34,35]. The doses of clozapine and risperidone were chosen on the basis of our previous work showing efficacy against sub-chronic PCP in the reversal learning paradigm [2,42] and NOR task [22].…”

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

“…In this study, we used doses of haloperidol or risperidone that achieve 80% or greater D2 receptor occupancy, therefore producing extrapyramidal symptoms that prove drug release and action. Since risperidone achieves D2 receptor occupancy less readily than haloperidol, it was administered in proportionally higher doses (2.13 mg/kg/day) relative to haloperidol (0.4 mg/kg/day) ( Kapur and Remington, 2001, Kapur and Seeman, 2001, Kapur et al, 2003and Wadenberg et al, 2001). This dosing regimen also takes into consideration the reported 4-6 times shorter half-life of antipsychotic drugs in rodents than humans and highlights the advantage of using minipumps in the present study for continuous drug administration to achieve receptor occupancies comparable to clinical use in humans (Kapur et al, 2003).…”

“…Since risperidone achieves D2 receptor occupancy less readily than haloperidol, it was administered in proportionally higher doses (2.13 mg/kg/day) relative to haloperidol (0.4 mg/kg/day) ( Kapur and Remington, 2001, Kapur and Seeman, 2001, Kapur et al, 2003and Wadenberg et al, 2001). This dosing regimen also takes into consideration the reported 4-6 times shorter half-life of antipsychotic drugs in rodents than humans and highlights the advantage of using minipumps in the present study for continuous drug administration to achieve receptor occupancies comparable to clinical use in humans (Kapur et al, 2003). Rats were group-housed (three rats of same treatment group per cage) and were fed a normal chow diet ad libitum (6% calories from fat, 21% calories from protein, 71% calories from carbohydrate, 2.6 kilocalories/g, Gordon's Speciality Stock Feeds, Yanderra, NSW, Australia).…”