PHARMACOGENETIC FACTORS IN PSYCHOPHARMACOLOGY

    The science of pharmacogenetics is complex, involving genetic differences in pharmacokinetic and pharmacodynamic factors in addition to issues of disease prevalence and cultural perceptions of both disease and treatment, all of which vary with age as well, regardless of age or ethnicity.  These factors can be particularly significant when treating patients with antipsychotic and antidepressant agents whose effective doses can vary wildly from one heterogeneic ethnic group to another.

Disease Prevalence
     The incidence, diagnosis, and treatment of mental health problems are similar among all races and cultural backgrounds, excluding the very poor and homeless groups, which are disproportionately represented by minorities.  Incidence of mental health problems is higher in lower socioeconomic groups, which places minority populations in general at greater risk.  Such populations are also less likely to seek appropriate mental health care, whether because of cultural pressures and beliefs or because of unavailability of such services or inability to pay for them.  So members of higher socioeconmic groups, regardless of race, are more likely to recognize mental health problems and the need to treat them; and they are more likely to have access to mental health care. Patients in lower socioeconimic groups tend to receive health care in the primary care setting, while the more affluent tend to be cared for by specialists in greater numbers, providing a significant difference in quality of care.
     These generalizations are statistically demonstrable, regardless of ethnic minority in the U.S. (of African, Asian/Pacific Island, or Hispanic descent), with exception of Native Americans.  Native Americans and Alaskan Natives suffer significantly more mental health problems than other minorities and Caucasians.  All such minorities face the barrier to proper care due to paucity of available health care workers able to speak their languages and identify with their particular cultural barriers to optimum care.

Genetic Therapeutic Factors
     In addition to those broad statements regarding cultural differences, genetic differences that affect large portions of various minority groups are responsible for some very significant differences in pharmacokinetics and pharmacodynamics that can dramatically affect the efficacy and safety of a number of medications in certain populations.  As an example, look at the widely-recognized phenomenon that makes beta-adrenergic blockade substantially less reliable at reducing blood pressure in black populations as a whole than in other races.  Such differences in efficacy may be due to availability or functionality of relevant drug receptors, drug transport systems, metabolic enzymes, or even some combination of those factors.
     While scientific study of most of those factors is currently limited, the Cytochrome P450 (CYP) microsomal enzyme systems located in the hepatic mitochondria have been studied extensively; and the impact on pharmacokinetics due to racial genetic differences is just beginning to be recognized and studied. With some 40 CYP systems identified to-date, the CYP2D6 system represents only a small relative proportion of such microsomal enzymes (around 2%), but this unique group of enzymes is involved in up to 40% of metabolic pathways of all medications used in current therapeutic regimens.  (See Table 1.)  Genetic variations in the expression of these particular enzymes (alleles) dramatically affect the efficiency by which these enzymes metabolize a large group of medications, leading to dramatic variations in the effectiveness of drug metabolism in various ethnic groups and thus corresponding variations in either prodrug activation or therapeutic blood levels, elimination half-lives, and drug interactions of affected medications.

Table 1:  Proportions of Medication Biotransformation Via Various Cytochrome P450 Enzyme Systems

 The clinician is referred to the RxFactStat/LECOM web site for more complete discussions on potential drug interactions involving the CYP enzyme systems and other mechanisms affecting these and other Drug Interactions.

     Differences in gene expression of these particular enzymes have been classified into phenotypes of rapid (or normal) metabolizers, intermediate metabolizers, and slow metabolizers, based on the efficacy of the enzymes produced in genetic populations.  Recognition of these groups and their occurrence in various minority populations is a key to effective and safe pharmacotherapy with a wide variety of medications, the psychopharmacological agents in particular.  A working knowledge of occurrence in particular minority populations is essential for successful psychopharmacotherapy.

Types of Cytochrome P450 Enzyme Drug Interactions
     Significant drug interactions involving the CYP450 enzyme systems can occur from competition between different agents for the same enzyme pathways.  A finite amount of specific enzymes (which can be dictated by genetic factors) can be overwhelmed by large amounts of multiple drugs that depend on the same enzyme pathway for biotransformation/metabolism.  
     Certain groups of medications (or exposures, like smoking) can either induce or inhibit various CYP enzyme systems.  Inducing factors typically enhance the ability of such enzyme systems to metabolize their substrates, shortening half-life, possibly AUC, and reducing blood levels and therapeutic response.  Inhibiting factors impair the ability of the given enzyme system(s) to metabolize normal substrates, resulting in abnormally elevated half-lives, AUC, blood levels, and both therapeutic response and side-effect potential.
     It is also important to recognize that while the antipsychotic agents are largely very lipophilic, in that they cross the blood/brain barrier to maximize concentration in lipid tissues (delaying elimination) and in cerebrospinal fluid.  They are also all highly protein-bound, which means that only the non-protein-bound fraction is available for transport, receptor binding, and metabolism.  Thus, high doses and broad therapeutic indices are the norm for this group of medications, with a usual ceiling dose beyond which little therapeutic benefit is seen.  Agents that displace these medications from their protein-binding sites can suddenly and significantly increase amounts of drug available for receptor binding, therapeutic effect, and side effects.  This is the reason for cautions against indiscriminate concurrent use with anti-seizure medications, of which several are notorious for protein-binding displacement.  This is as-yet an inexact science regarding these medications, so caution is the watchword with concurrent therapy.

Mental Health:  Culture, Race, and Ethnicity.  Executive Summary.  U.S. Department of Health and Human Services Publication

Bradford, L.  CYP2D6 allele frequency in Euyropean Caucasians, Asians, Africans, and their descendants.  Pharmacogenomics. 2002 3(2)