New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects.
BACKGROUND
Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy ["therapeutic index" (TI)] has fit well with clinical results.


OBJECTIVE
1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine's neuropharmacology.


METHODS
Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI.


RESULTS
Excepting clozapine and DOD 647, all drugs induced dystonia. At 2-4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3-5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses.
Peacock
L
L
Institute of Biological Psychiatry, St. Hans Hospital, Roskilde, Denmark.
Gerlach
J
J
D000661:Amphetamine / Q000037:antagonists & inhibitors*; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D002428:Cebus; D003024:Clozapine / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D003913:Dextroamphetamine / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology; D004421:Dystonia / Q000139:chemically induced*; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000188:drug therapy
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D000661:Amphetamine; D003024:Clozapine; D003913:Dextroamphetamine