Psychopharmacology: Cross-Cultural Psychopharmacology: A Current Clinical Perspective

During the past four decades the population of the United States has become increasingly multiethnic and multicultural. Physicians increasingly need to understand the role of ethnicity and culture when diagnosing and providing psychiatric care to ethnically, culturally, and linguistically diverse populations. The field of cross-cultural psychiatry and psychopharmacology has grown immensely to help meet this need. Cross-cultural psychopharmacology seeks to determine whether differences exist between ethnic groups in their response to psychotropic medications, as well as the reasons for such variations, including genetic, biological, environmental, and psychosocial factors. Interest in this area has been piqued with the discovery of genetic polymorphisms in the cytochrome P-450 (CYP) enzyme systems that are responsible for metabolizing most psychotropic medications. However, research studies examining the cross-cultural aspects of psychotropic medications have often yielded conflicting findings, and many questions remain unanswered.

Ethnicity and culture in diagnosing and treating psychiatric disorders

Diagnostic issues

Culturally determined health beliefs and practices can profoundly affect psychiatric assessment and pharmacotherapy. For example, patients from ethnic minority groups often present with somatic rather than psychological complaints or may have culturally shared beliefs that may be mistaken as delusions. Clinicians who are unfamiliar with a patient's culture and health beliefs may misinterpret symptoms, leading to diagnostic errors. African-American patients who present with mania, depression, or alcohol-related symptoms are often misdiagnosed as having schizophrenia (1). Compared with whites, African Americans are more likely to receive a diagnosis of schizophrenia when presenting to psychiatric emergency departments (2).

Cross-cultural differences in psychotropic use

The types and dosages of psychotropic medications may differ significantly in different countries or regions or even in the same clinical setting. African-American patients may be less likely than white patients to receive second-generation antipsychotics or selective serotonin reuptake inhibitors (3,4). Among veterans with schizophrenia, overall use of second-generation antipsychotics has been reported to be slightly less common, and use of clozapine much less common, among African Americans and Hispanics than among whites (5). Because patients from ethnic minority groups may not receive first-line recommended treatments, they may have less clinical improvement than white patients and be exposed to a greater risk of side effects, including extrapyramidal symptoms. Differences in prescribing patterns may also contribute to the lower rates of adherence and to the more frequent emergency department visits and psychiatric hospitalizations that have been reported among African Americans (6).

Some reports have indicated that Asians and Hispanics typically require lower dosages of psychotropic medications than whites (7,8), although others have noted conflicting findings (9,10). A frequently cited study by Lin and Finder (7) found that Asians required lower dosages of chlorpromazine equivalents than whites, although the overall dosages were very high: Asians received a mean of 1,000 mg equivalents daily and whites received more than 2,000 mg equivalents daily. During the same period, less than 20 miles from the study location, a research team used a mean dosage of 355 mg of chlorpromazine to treat a group of similar non-Asian inpatients (11), suggesting that providers' practicing habits are largely responsible for noted dosage differences. African Americans, in both inpatient and outpatient settings, often receive higher dosages of antipsychotic medications (1,2,12,13) and are more apt to be prescribed long-acting depot preparations (4,14). However, a more recent study from Great Britain found that dosages of two widely used second-generation antipsychotics, olanzapine and clozapine, did not differ significantly between Asians, African Americans, and whites (15).

Some cross-cultural differences have been reported for therapeutic and side effects of psychotropic medications. One study found that compared with whites, Asians manifested significantly more extrapyramidal side effects from haloperidol during an initial fixed-dose phase. The study also found that Asians required significantly smaller doses during the clinically determined, variable-dose phase, resulting in lower plasma concentrations of haloperidol for an optimal response (16). This and other studies imply that Asians should receive lower dosages of antipsychotics because the therapeutic and extrapyramidal effects of these medications may occur at a lower percentage of dopamine receptor blockade. These studies also suggest that genetically determined biological factors are important to consider when using these psychotropics. However, increased rates of side effects may be secondary to incorrect diagnoses or to the higher dosages of medications given to certain ethnic groups. For example, the fact that African Americans are more frequently given prescriptions for first- rather than second-generation antipsychotics and that they receive higher dosages of these medications may account for the observation that they may be more sensitive than whites to antipsychotic side effects, including tardive dyskinesia (1,17,18,19). Thus both genetic and environmental factors need to be considered in the cautious use of antipsychotic medications (20,21).

Factors influencing pharmacologic differences

Although numerous anecdotal clinical reports have suggested that ethnicity and culture significantly influence the dosage requirement and side effect profiles of various psychotropic medications, few systematic, rigorously designed studies have explored the potential mechanisms that are responsible for these differences. Variations between different ethnic groups may be due to genetic and biological differences in pharmacokinetics (that is, factors related to how the body handles drugs, such as protein-binding absorption, distribution, metabolism, and excretion) or in pharmacodynamics (that is, factors related to the effect of a drug on the body, such as receptor-coupled response or tissue sensitivity). Cross-cultural variations in psychotropic use may be secondary to environmental and psychosocial factors, such as diet; personality traits; patient compliance or adherence; placebo effects; patients' and family members' attitudes toward pharmacotherapy; societal demands and tolerance of psychiatric symptoms; physicians' diagnostic skills, prescribing habits, and attitudes toward pharmacotherapy; and the costs and availability of medication, other treatments, professionals, and facilities (22).

Biological considerations in psychopharmacology

Some well-defined pharmacogenetic differences exist between ethnic groups. One of the best known of these involves ethanol metabolism. Evidence supports that there are some ethnic differences in the effects of psychotropic medications, which may result in dissimilar rates of response and side effects. Pharmacokinetic differences between ethnic groups have received the most study, although pharmacodynamic factors have also been implicated.

Differences in the plasma proteins that transport medications have been reported among ethnic groups. The plasma concentration of (α₁-acid glycoproteins, which provide binding sites for psychotropic drugs in the blood, was found to be significantly lower among Asians than among whites and African Americans (23). The activities of conjugating enzymes (transferases) that are involved in the metabolism of most psychotropic medications are now known to be genetically determined. The CYP system has been found to demonstrate genetic polymorphism and to exist in a bimodal distribution; individuals may be classified as extensive, poor, or slow metabolizers, depending on whether they carry genetic mutations that produce alterations in the enzymes' amino acid structure and activity (24,25). The genetic polymorphism and subsequent functional expression of CYP enzymes, particularly CYP2D6 and CYP2C19, may contribute to differences in rates of psychotropic medication metabolism. In addition to these genetic differences between ethnic groups, interethnic differences in enzyme activity may exist, partly resulting from a variety of environmental factors, such as diet, use of herbal medicines, and other lifestyle factors.

Currently, although complete evaluations of the expression of the CYP enzyme can be readily performed and may be clinically useful, they may reveal little to the prescribing physician about the patient. One clinical implication of being able to evaluate the CYP enzyme is that drug interaction considerations that are related to the enzyme would be able to be determined. Another immediate clinical implication is that rates of metabolism would be able to be determined. Even when recommended dosages of medication are prescribed, slow metabolizers may be at an increased risk of side effects or toxicity as a result of elevated plasma concentrations, whereas extensive metabolizers may not benefit from usual dosages as a result of subtherapeutic plasma concentrations.

Environmental and psychosocial factors

Many environmental or psychosocial factors must be considered when trying to explain observed cross-cultural differences in the use of psychotropics. Patients of different ethnic groups and their treating physicians may have different medication or treatment preferences, with concerns over potential serious side effects, such as agranulocytosis or hyperglycemia (5). Physicians who treat patients from ethnic minority groups may also have different knowledge, skills, and attitudes (26). Differences in treatments among ethnic groups may also be related to economic and health-system factors (6). For example, recently reported racial disparities in pharmacologic treatment among Medicaid recipients may be related to lack of or limited access to mental health services by ethnic minority groups (3,27). Similarly, newer psychotropic medications may be less likely to be prescribed when clinically indicated to save cost (28,29).

Conclusions

Ethnic and cultural issues are becoming increasingly important in the field of psychopharmacology. Observed variations among ethnic groups in the use of different treatment modalities, medications, and dosages and in estimates of both therapeutic and side effects may be greatly influenced by biological and psychosocial factors. Data from systematic, scientifically designed studies are beginning to probe the existence and clinical significance of pharmacogenetic differences among various ethnic groups (22,30). Cultural factors are also being investigated, including culturally determined behaviors and societal circumstances.

Future studies must be based on evidence and empirical data to determine whether differences in the use of and response to psychotropics are due to genetic factors or environmental factors, or both. Physicians will need to be increasingly aware of these factors in their approach to ethnically disparate patient populations and the use of psychotropic medications. The most appropriate evidence-based pharmacotherapy must always be provided. For the moment, physicians should adhere to the basic principle of rational psychopharmacotherapy, that is, to prescribe the lowest possible effective dose for the shortest duration, maximizing therapeutic effects while minimizing side effects (31). Mega-dose practice, based on a more-is-better philosophy, should be avoided. Pharmacotherapy plans should be individualized, taking target symptoms and side effect profiles into consideration for patients from different ethnic and cultural backgrounds. These principles should be applied to everyone regardless of his or her ethnic or cultural background. The ultimate goal is an integrative approach in which biological, ethnic, and cultural diversity are taken into account and treatment is tailored to specific individual characteristics.

Dr. Pi is affiliated with the department of psychiatry and biobehavioral sciences in the David Geffen School of Medicine at the University of California, Los Angeles, and with the department of psychiatry at Harbor-UCLA Medical Center, 1000 West Carson Street, Box 8, Torrance, California 90509. Dr. Simpson, who is editor of this column, is with the department of psychiatry and behavioral sciences at the University of Southern California in Los Angeles.