Elsevier

Biological Psychiatry

Volume 64, Issue 2, 15 July 2008, Pages 145-152
Biological Psychiatry

Archival Report
Less Is More: Antipsychotic Drug Effects Are Greater with Transient Rather Than Continuous Delivery

https://doi.org/10.1016/j.biopsych.2008.01.010Get rights and content

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 (∼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.

Section snippets

Methods and Materials

Male Sprague Dawley rats (Charles River Laboratories, Montreal, PQ, Canada) weighing 225 g to 250 g were housed two per cage in a climate-controlled colony room with a 12-hour reverse light/dark cycle (lights off at 8:00 am). Food and water were available ad libitum. All testing was conducted during the dark phase of the animals' circadian cycle and was in compliance with the institute's animal care committee.

Experiment 1: Effects of the kinetics of HAL Treatment on Behavioral Sensitivity to AMPH Over Time

In Experiment 1, we examined the effects of the kinetics of chronic antipsychotic drug administration (achieved by administering HAL via minipump or daily SC injection) on the suppression of AMPH-induced locomotion over time. The locomotor response to AMPH in the HAL-.05 CONT rats was not different from control animals at any time point tested. Early in treatment (day 2; Figure 2A), AMPH-induced locomotion was suppressed in both the HAL-.5 CONT and HAL-TRANS groups to a similar degree. With

Discussion

We show here that chronic treatment with an antipsychotic, using the same achieved dose and route of administration but different treatment kinetics (i.e., within-day continuous versus transient), leads to tolerance to ongoing antipsychotic treatment in one case and progressively increasing efficacy in the other. Transient treatment was more effective than continuous treatment even when a 10-fold lower dose was administered using the transient mode, thus producing greater efficacy with lesser

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