Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery.
BACKGROUND
Most studies on the effects of antipsychotics focus on achieving threshold levels of the drug. The speed and frequency with which drug concentrations reach threshold levels and rise and fall within the day are generally ignored. Based on prior data, we predicted that variations in the within-day kinetics of antipsychotic drug delivery would produce different outcomes, even if we held achieved dose, route, and total duration of treatment constant.


METHODS
We compared the effects of within-day continuous (via minipump) versus transient (via subcutaneous injection) haloperidol treatment (n = 4-9/condition/experiment) at doses that yield equivalent peak levels of striatal D2 receptor occupancy (approximately 74%).


RESULTS
Over time, transient haloperidol gained efficacy, while continuous haloperidol lost efficacy in two animal models of antipsychotic-like effects (the suppression of amphetamine-induced locomotion and conditioned avoidance responding). This was related to the fact that continuous treatment led to a greater increase in striatal D2 receptor numbers--particularly D2 receptors in a high-affinity state for dopamine--relative to transient treatment and produced behavioral dopamine supersensitivity (as indicated by an enhanced locomotor response to amphetamine following antipsychotic treatment cessation). Treatment kinetics also influenced the postsynaptic response to haloperidol. Transient treatment increased striatal c-fos messenger RNA (mRNA) expression, while continuous treatment did not.


CONCLUSIONS
Relative to continuous antipsychotic exposure, within-day transient exposure is more efficacious behaviorally and is associated with a distinct molecular and gene expression profile. Thus, differences in the within-day kinetics of antipsychotic treatment can have different efficacy, and the potential clinical implications of this should be explored further.
Samaha
Anne-Noël
AN
Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Reckless
Greg E
GE
Seeman
Philip
P
Diwan
Mustansir
M
Nobrega
José N
JN
Kapur
Shitij
S
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001362:Avoidance Learning / Q000187:drug effects; D001682:Biological Availability; D003214:Conditioning, Classical / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D006220:Haloperidol; D003913:Dextroamphetamine