Commentary

by L. DiAnne Bradford*

DBP3.jpgThe basic principles underlying "personalized medicine" require a prescribing physician take into account not only empirically based guidelines, but also the individual characteristics of the person needing therapy. In deliberations about whether or not drug therapy is warranted, the selection of drug, dosing, and the benefit to risk must be weighed for each patient. Special dosing considerations for the elderly, children, and pregnant women are already in common practice for both prescription and over-the-counter (OTC) drugs, and drug selection. There is reason to believe a similar consideration should be given for differences based on race.

Empirically based guidelines for drug, dosing, efficacy and safety are based on extensive psychopharmacological research and clinical trials. Drug studies fall generally under two categories: pharmacokinetics (how the body affects the drugs, i.e., how the drug is metabolized); and pharmacodynamics (how the drug affects the body, i.e., efficacy and safety). The early stages of drug development (Phase I) determine the pharmacokinetics of the drug and lay the basis for the selection of doses for efficacy and safety studies (Phase II and III). Current practices rely predominantly on evidence from research from people of European Caucasian descent. Clinical studies showing how the body metabolizes a drug in African Americans, Asian Americans and other minorities in the United States, are rare. Drug development -- Phase II and III studies -- establishing efficacy and safe dose ranges, are conducted predominantly in Caucasians (world wide). Again, African American participants are notably under-represented.

Differences in metabolizing drugs
Ethnopsychopharmacology and pharmacogenetic studies, respectively, show how and why people of different racial and/or ethnic origin may respond to drugs differently. These studies, over the past twenty years, indicate that people of Asian descent metabolize some antidepressants and antipsychotic drugs more slowly than Caucasians. Research in people of African descent is more recent and not nearly as comprehensive. In spite of a growing scientific literature indicating that people of African and Asian descent may respond differently to psychotropic drugs, presently used guidelines do not consider these differences.

Ethnopsychopharmacology and pharmacogenetic studies
The process by which genes play an important role in metabolizing drugs can be summarized this way: Genetic material (DNA) directs the production of proteins. These proteins form the basic building blocks for enzymes (which can either make or break down substances), receptors (which act as receivers of neuronal information), growth factors, and transporter systems for the chemical messengers. Some genes are involved in how the drug is metabolized (pharmacokinetics), while others influence how the individual will respond (how well the drug works and the side effects). Ethnopsychopharmacology studies identify clinical characteristics of psychotropic drug response that are special for certain racial and/or ethnic groups (e.g., pharmacokinetics, efficacy and side effects). After a difference in response is observed, pharmacogenetic studies try to identify the genetic variations underlying these unique characteristics.

Pharmacokinetic (drug metabolism) findings
In the 1980s, clinical observations of large variations in response to tricyclic antidepressants - ranging from no response to severe side effects - initiated extensive studies in Europe that identified variations in the gene responsible for metabolizing these drugs. Most drugs in common clinical use are metabolized in the liver by a family of enzymes. One of these, CYP2D6, is responsible for metabolizing many of the tricyclic antidepressants, a few second generation antidepressants, many of the conventional antipsychotics (e.g., haloperidol, Haldol®), and two of the atypical antipsychotics, risperidone (Risperidone®) and aripiprazole (Abilify®).

A variation in the genetic material forming the CYP2D6 gene was observed in early pharmacogenetic studies, based on differences in clinical response to tricyclic antidepressants. Genetic material, DNA, determines the rate of metabolic activity. If the enzymes are fully functional, the person is an extensive (normal) metabolizer. Changes in the DNA material can alter the rate of metabolism. There are at least three categories for this: (1) If a person had duplications of this genetic material, he or she would metabolize the drug so quickly that therapeutic levels of the drug could never be reached. This is called ultrarapid metabolism. (2) On the other hand, someone can inherit genetic material which produces none of the desired enzyme, so that person will not be able to metabolize a drug at all; this person would be a poor metabolizers. (3) If a person carried genetic material that codes for less CYP2D6 enzyme activity than normal, he would be an intermediate metabolizer, and metabolize the drug very slowly. People are intermediate and poor metabolizers often have more severe side effects.

Many of these pioneer pharmacogentic studies were conducted in Sweden, where a large population of Chinese immigrants lived near the university and forward thinking researchers conducted a comparative pharmacogenetic study. They observed that the Chinese population metabolized drugs involving the CYP2D6 enzymes considerably slower than did Caucasians, but there were far fewer (about one percent) poor metabolizers. Further, pharmacogenetic studies revealed unique genetic variations, polymorphisms, in the Chinese group. They discovered a new genetic variation which results in reduced enzyme activity, and which is very common in people of Asian descent, yet rare in Caucasians. Further, they found that the genetic variation in Caucasians which is responsible for most poor metabolizers in that population, CYP2D6*4, is very rare in Asians, accounting for fewer poor metabolizers.. Subsequent studies in Asians have been conducted primarily in China, Japan and Korea, and clearly establish that about 40% of Asians are "intermediate metabolizers" as a result of the high frequency of CYP2D6*10. This has also been associated with increased side effects (e.g., movement disorders) of antipsychotic drugs which are metabolized by CYP2D6.

Meanwhile, pharmacogenetic studies in African also showed unique genetic variations. For example, studies conducted in Zimbabwe identified another "reduced function" genetic variation (CYP2D6*17), which occurs frequently in people of African descent, and is responsible for slower metabolic rate. A number of other genetic variations which result either in reduced or non-functional CYP2D6 enzyme activity, and are unique to people of African descent, have been identified by researchers, including Morehouse School of Medicine's collaboration with Children's Mercy Hospital's Dr. Andrea Gaedigk (U of Mo).

Studies using drugs metabolized by CYP2D6 show that many people of African descent - like those of Asian descent - metabolize these drugs more slowly than Caucasians. Therefore, it is predicted that when prescribed the same doses as Caucasians, about 40% of people of African descent will have higher blood levels of drugs metabolized by CYP2D6. Higher blood levels of psychotropic drugs relate more to side effects (e.g., sedation, cardiovascular effects, movement disorders) than they do for efficacy, increasing the burden or risk associated with these drugs. Yet, there are no available studies in people of African descent that could indicate appropriate choice and drug dose.

Pharmacodynamic studies
An individual's genetic material can also influence how effective a psychotropic drug will be in reducing the symptoms of the psychiatric illness, and determine the occurrence and/or severity of side effects. The examples above show that a person's unique genetic make-up can determine how quickly or slowly a drug will be metabolized.

The way in which psychotropic drugs work is through targeting enzymes, receptors, neurotransmitters (the chemical messengers), proteins and other building blocks of the central nervous system. Pharmacogenetic studies in Caucasians and Asians indicate that a genetic variation in a receptor involved in atypical antipsychotic drugs' mechanism of action (how they work) may determine whether the person will gain weight or not. This genetic variation may differ between people of difference race/ethnicities.

A recent report from a large NIMH-sponsored study on the efficacy and safety of antipsychotic drugs in people diagnosed with schizophrenia showed that a genetic variation in a protein, which is responsible for regulating several kinds of receptors, is associated with how well a person will respond to specific antipsychotic drugs. African Americans with a certain variation in the gene responded particularly well to two of the antipsychotic drugs, while symptoms worsened with another drug. Variations of this gene in Caucasians predicted a good response to yet another one of the drugs.

The future of personalized medicine
It is clear from the past decade of study that we are making progress in determining that genetic variations in individuals can and do impact drug response. In order to truly offer personalized medicine advantages for all Americans, more emphasis needs to be placed on determining genetic variations not only of people of European Caucasian descent, but also in people of African and Asian descent. At the present time, there are no federal (FDA) guidelines requiring pharmaceutical companies to conduct studies in minority populations.

Pharmaceutical companies have been reluctant to conduct studies in minority populations that may show differences in efficacy and/or side effects, since this would affect their mass, nationwide direct-to-consumer advertising. It is also clear that the pharmaceutical industry requires incentives to do these studies. For example, the industry has been motivated to conduct clinical trials in children and adolescents by prolonging the patent on the drug. The push for these changes is not coming from within the government or the pharmaceutical industry, so they must come from consumers.

* L. DiAnne Bradford, Ph.D., is the Director, Minority Mental Health Research Program, Department of Psychiatry, Morehouse School of Medicine. She has written extensively about mental health in African Americans. Her current research includes determining the genetic etiology and cognitive deficits in African Americans with schizophrenia, and depression in African Americans.

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