Slow onset of CNS drugs: can changes in protein concentration account for the delay?

Trends Pharmacol Sci. 2001 Sep;22(9):450-6. doi: 10.1016/s0165-6147(00)01776-4.


A 'protein regulation hypothesis' might explain the delay in reaching a maximal clinical effect, exhibited by some antipsychotic and addicting drugs. It also suggests that crucial 'effector' proteins that mediate the actions of these drugs might have half-lives of days to weeks. In this article, the rate of onset of some antipsychotic and addicting drugs will be examined and a model will be used to test if a change in the concentration of a given protein(s) could cause the drug-induced effects. This hypothesis uses a model where protein concentrations are determined by a zero-order synthesis rate and a first-order degradation rate. The model in its simplest form produces an exponential increase (or decrease) in protein concentrations over time, but reasonable extensions of the model can account for more complex mechanisms that allow for delayed time-courses and contributions of multiple proteins to the clinical effect.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Antipsychotic Agents* / metabolism
  • Antipsychotic Agents* / pharmacokinetics
  • Antipsychotic Agents* / therapeutic use
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism*
  • Half-Life
  • Humans
  • Models, Biological*
  • Proteins / physiology*
  • Substance-Related Disorders / metabolism*
  • Time Factors


  • Antipsychotic Agents
  • Proteins