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

doi:10.1016/S0165-6147(00)01776-4

Trends in Pharmacological Sciences

Volume 22, Issue 9, 1 September 2001, Pages 450-456

https://doi.org/10.1016/S0165-6147(00)01776-4 Get rights and content

Abstract

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.

Section snippets

Temporal delay of antipsychotics and opiates

The temporal delay to full effect, or the gradual onset for antipsychotics and addicting drugs, is well documented. Results vary depending on the drug, dosing regimen, species, end-points and other factors, but the delay to full drug effect can be many weeks. The drugs are given repeatedly and the time-courses of clinical effects start with the beginning of dosing (zero or one on the x-axis). When possible, the data selected for consideration were from a middle dose of a dose–response set

A model for an increase (or decrease) of protein concentration over time

Because the above-mentioned drugs require weeks to produce maximal effects, a proposed mechanism should account for this delay. The model considered here predicts the time-course of changes in the concentration of a protein following a drug-induced change in its synthesis or degradation rate, acknowledging that changes in protein concentrations might follow from changes in gene expression and/or mRNA stability. The model is well known and assumes that protein synthesis follows a zero-order

Case I: a single protein as effector

Case I (Fig. 3a) is the simplest situation (Eqn Eq. (1)). However, it should be noted that other factors could make a difference to the shape of the time-of-onset curves for a single protein effector. For example, if a certain ‘threshold’ concentration of the protein were needed to produce its effect, a delay in the time for the appearance of the effect would be evident (this could also be explained by Case III, described below). Similarly, if the maximal concentration of a protein were not

Compatibility of the data and the model

The crux of this approach is to attempt to fit curves generated by the model to experimental data. If there is a reasonable fit, one can hypothesize that, and test if, the assumptions used to build the model apply to the data. Considering the antipsychotic data in Fig. 1, there is an excellent fit between the data and a curve for a single protein generated by computer (Fig. 4). The half-life of the putative effector protein would be ∼30 days for the clozapine data (Fig. 4b) and less for the

Protein half-lives

The formulation of the model has been in terms of the half-lives of proteins instead of their rates of synthesis or degradation, although the latter are implicitly involved. Half-life was selected as the focus because it is compatible with the time-of-onset problem, which is the particular issue addressed here. It is clear from the discussion above that involvement of proteins with half-lives of days to weeks would make the data compatible with the considered model. Do proteins with such

Concluding remarks

This study emphasizes the need for a mechanism to explain the temporal delay of weeks for the considered drugs, and proposes a ‘protein regulation’ model that will be helpful in analyzing and evaluating candidate mechanisms. Indeed, many have suggested that changes in brain proteins mediate the long-term effects of various drugs 7, 8, 9, 10, 28, 29, 30. The results here are compatible with these suggestions but add a quantitative tool for consideration. We were led to a consideration of this

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Trends in Pharmacological Sciences

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

Abstract

Section snippets

Temporal delay of antipsychotics and opiates

A model for an increase (or decrease) of protein concentration over time

Case I: a single protein as effector

Compatibility of the data and the model

Protein half-lives

Concluding remarks

Brain Res.

Brain Res.

Brain Res.

Neuropharmacology

Drug Alcohol Depend.

Neuron

Drug Alcohol Depend.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Jpn. J. Pharmacol.

Initiation and adaptation: a paradigm for understanding psychotropic drug action

Am. J. Psychiatry

Transcription factors in the central nervous system

Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins

Brain Res. Rev.

Pattern of c-fos mRNA induction in rat brain by acute morphine

Can. J. Physiol. Pharmacol.

Region-specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs

Synapse

Drug addiction and drug abuse

Enzyme expansion theory of drug tolerance and physical dependence

Res. Publ. Assoc. Res. Nerv. Ment. Dis.

Molecular pathology of schizophrenia: more than one disease process?

Br. Med. J.

Antipsychotic drugs

Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome

Am. J. Psychiatry

Time course and biologic correlates of treatment response in first-episode schizophrenia

Arch. Gen. Psychiatry

Time to clozapine response in a standardized trial

Am. J. Psychiatry

Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats

Psychopharmacologia

Quantitative method for assessing one symptom of the withdrawal syndrome in mice after chronic morphine administration

Nature

Development and maintenance of morphine tolerance and dependence in the rat by schedule access to morphine drinking solutions

J Pharmacol. Exp. Ther.

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