An hypothesis of initial conditions: receptor-effector systems as determinants of psychopharmacologic drug response

A variety of biological factors have been sought to explain why psychopharmacologic drug response varies between patients. In addition to variables such as age, race, gender, age of onset, severity, number of previous episodes, prior drug treatment, comorbidity and hormonal state, there have been investigations also into a variety of pharmacokinetic and pharmacodynamic variables such as dose, absorption, metabolism, distribution, globulin/protein binding, excretion and rate of titration, all potentially considered to explain differences in drug response. However, it is clear that, in many cases, such variables do not fully account for differences in drug response. In this work, it is hypothesized that drug response may also be significantly determined by the initial conditions of receptor site kinetics, as well as the sensitivity of downstream receptor-linked responses. This theory of initial conditions suggests that drug-action depends on receptor affinity and capacity, as well as on the conditions determining gene regulatory factors, which may influence transcription of gene products related to the emergent drug properties mediated through the receptor. Under one such scenario, dose response would be related, in the expected direction, to the initial affinity conditions of the receptor. For example, if the net effect of a drug were to decrease the apparent affinity of the receptor for its endogenous ligand, a stronger response could then be expected within a lower dose range, for those cases in which the initial affinity conditions for the receptor are already lower. The principle of initial conditions may apply not only to therapeutic psychotropic drugs, but also to drugs of abuse. This work reviews evidence to date in support of initial receptor conditions determining response to antipsychotic agents, response to antidepressants, and dependence as a response to alcohol, as conceptual examples.