PSYCHOPHARMACOLOGY:

CULTURAL AND ETHNICAL

PERSPECTIVES
PRESENTER: DR. POONAM Y. NAIK
MODERATOR: DR. Y.S. PEREIRA
OVERVIEW

 INTRODUCTION
 DEFINITIONS
 MECHANISMS AFFECTING DRUG RESPONSE
 BIOLOGICAL FACTORS
 NON BIOLOGICAL FACTORS
 REFERENCES
INTRODUCTION

 Since the inception of the modern era of

psychopharmacology, psychotropics have been the
mainstay of the care of psychiatric patients all over the
world, irrespective of their cultural and ethnic
backgrounds.

 Until recently, however, variations in treatment response

across populations, including effectiveness, dosing
strategies, and adverse effect profiles, have received
minimal attention.
 Psychopharmacological research in general and RCT in
particular have been conducted largely in North America
and Western Europe and have rarely included persons of
ethnic minority or cross cultural backgrounds.

 Biases also lie in the assumptions that suggests that

treatment responses are predominantly determined by
biological mechanisms and that biological processes are
universally applicable and thus color and culture free.
 In addition to ethno-biological determinants of drug
response, there are significant cultural factors:

 The concurrent use of pluralistic health systems.

 Alternative therapies and folk remedies which might

support, hinder or complicate pharmacotherapy.

 Treatment adherence.
 The therapeutic effect of pharmacologically active drugs is
determined by pharmacokinetic and pharmacodynamics
processes.

 A pharmacogenetic variation according to the ethnic group

can lead to significant genetically determined modifications
of metabolizing enzymes.

 This in turn leads to differing therapeutic levels and half lives

and therefore variable profiles of therapeutic adverse effects.
DEFINITIONS

 ETHNICITY: Self or social ascription of belonging to a group

with common geographical origins, race, language, religion,
etc., which transcends kinship and neighborhood.

 Retain a strong racial component.

 Social group characterized by distinctive tradition, common

history and maintained within the groups across
generations.
 Race-Largely perceived by appearance and attributed to
biological and genetic traits.

 Racial differences get perpetuated in society because they

have cultural significance.

 Culture - Shared system of concepts or mental

representations established by convention and reproduced
by traditional transmission.

 People live culturally rather than in cultures.

 Pharmacokinetics - The study of how a biological organism
affects the fate and distribution of a drug.

 This is determined by four processes - absorption,

distribution, metabolism and excretion.

 The processes of metabolism exhibit substantial cross-

ethnic, as well as individual differences.

 Height, weight, differences in gastric acidity and percentage

body fat are all affected by race and culture can also affect
the pharmacokinetics of drugs.
 Pharmacodynamics - The study of the effects of a drug on the
person.

 It refers to the neurotransmitter, neurophysiological,

behavioral, psychological and social effects of psychotropic
drugs and their mechanisms of action.
 MECHANISMS AFFECTING DRUG RESPONSE
 The biological effects of pharmacologic agents are determined by
pharmacokinetic and pharmacodynamics processes.

 The pharmacokinetics of most drugs are determined by four

basic processes: absorption, distribution, metabolism and
excretion.

 Of these, the process of metabolism in particular has been

identified as frequently showing substantial inter-individual and
cross-ethnic variation and has been a major focus of research in
pharmacology.
 Non-biological factors may exert even more significant influence
on how an individual responds to medications.

 These include:
 personality,
 compliance,
 placebo effects,
 stress,
 social support,
 physicians’ prescription styles.

 Culture and ethnicity are thought to be important factors

influencing these variables.
ETHNICITY AND PHARMACOGENETICS

 Flushing response in a large number of Asians when

exposed to alcohol.

 Among Asian immigrants residing in the United States, was

found to exist in more than 50% of Eastern Asians Central
and South American Indians.

 Rapid facial flushing, dizziness, palpitation, nausea and

other uncomfortable symptoms after imbibing even a very
small amount of an alcoholic beverage.
 Genetically determined deficiency of aldehyde
dehydrogenase, which is accentuated further in some
individuals by an over activity of alcohol dehydrogenase.

 The end result of these changes is the rapid accumulation of

acetaldehyde, which is highly toxic and capable of inducing
all the symptoms listed above.

 In fact, the therapeutic basis of disulfiram (Antabuse) is

based on its ability to block the activities of acetaldehyde
dehydrogenase.
 THE CYTOCHROME P-450 ISOZYMES

 With the exception of lithium, the majority of psychotropics

as well as many non-psychotropic drugs) are highly
lipophilic.

 In order for these medications to be excreted from the body,

they must be made water soluble first.

 This is usually achieved in two phases, termed

functionalization and conjugation.
 Functionalization, accomplished by oxidation, directly
modifies the structure of the molecule itself.

 Conjugation involves the combining of the target molecule

with endogenous substances such as glucuronic acid and
sulfate.

 Since functionalization (oxidation) usually precedes

conjugation, the former is often called phase I, and the latter
phase II, of drug metabolism
 The metabolism and detoxification of the majority of
modern chemotherapeutic agents as well as a large number
of foreign substances are usually first achieved through
oxidation by a group of isozymes belonging to the
cytochrome P-450 system.

 It is estimated that more than twenty P-450 isozymes exist

in human beings.

 Each enzyme is encoded by a specific gene.

 The phenotypes (the activities of the enzymes) and genotypes
(the structure and function of the encoding genes) of some of
these P-450 enzymes also manifest distinct interindividual as
well as cross-ethnic variations.

 Such diversity is most clearly seen in two extensively studied

P-450 isozymes, namely, the CYP2D6 (debrisoquine
hydroxylase) and the CYPmp (mephenytoin hydroxylase).
 In any given population, they have been found to be
bimodally distributed, with a certain proportion classified as
poor metabolizers (PMs), who are deficient in the activities
of these respective enzymes.

 In contrast, those classified as extensive metabolizers (EMs)

do not have such deficiencies.
 As compared to EMs, PMs of CYP2D6 exhibit significantly
higher serum concentrations of a large number of tricyclic
antidepressants, selective serotonin reuptake inhibitors
(SSRIs) and neuroleptics, when given comparable doses of
the medication.

 Similarly, PMs of CYPmp show significant differences in the

metabolism of diazepam
ETHNICITY AND PHARMACOKINETICS

 Conjugation: Contrary to earlier beliefs, recently emerging

data indicate that conjugated compounds may play a
significant role in determining the clinical or adverse effects
of medications such as haloperidol.

 Mechanisms involved in the control of conjugation remain

largely unexplored.

 Little is known regarding ethnic differences in conjugation.

 Distribution: As most psychotropics are highly lipophilic, they
generally have a large volume of distribution, the size of
which is a reflection of the body composition, especially the
proportion of fat to water.

 Diversity in body build across ethnic groups is expected to

lead to differences in the volume of distribution and thus the
pharmacokinetics of drugs that are lipophilic.

 This in fact has been identified as one of the reasons for the
greater effect of diazepam in Asians as compared to
Caucasians.
 The distribution of lithium across cellular membranes is
controlled by several membrane transport and counter
transport mechanisms.

 Among these, the sodium-lithium counter transport system

appears to play a particularly important role.

 This system is significantly less active among African-

Americans and African Blacks as compared to Caucasians,
which might contribute to the higher prevalence of
hypertension as well as higher RBC/serum lithium ratio
among Blacks.
 Since intracellular concentration of lithium may determine its
clinical and side effects, ethnic differences in the RBC/serum
lithium ratio may have important clinical significance.

 In a recent study conducted by our group, significant

differences in the lithium ratio were found between African-
American and Caucasian bipolar patients, which were
correlated with a higher rate of CNS related side effects in the
former group, suggesting that the higher lithium ratio in this
group might indeed lead to higher central toxicity.
ETHNICITY AND PHARMACODYNAMICS

 Clozapine-induced agranulocytosis has been reported to be

significantly more prevalent among Ashkenazi Jews,
especially among those possessing a special cluster of
human lymphocyte antigen (HLA) typings that are frequently
found in this group.

 Ethnic differences in therapeutic concentrations of lithium,

haloperidol and tricyclic antidepressants and their
neurohormonal effects also are likely determined by
pharmacodynamics mechanisms.
ETHNICITY AND PSYCHOTROPIC DRUG RESPONSE

 NEUROLEPTICS .
 The pharmacokinetics and pharmacodynamics of haloperidol
have been demonstrated to differ significantly between
Asians and Caucasians.

 When given comparable doses of medication, Asian

schizophrenic patients and normal volunteers exhibited
plasma haloperidol concentrations that were approximately
50% greater than their Caucasian counterparts.
 Asians have lower ratios of reduced haloperidol/ haloperidol,
suggesting that a slower rate of reduction (a major
metabolic pathway for haloperidol) in Asians might be
responsible for the slower rate of metabolism, and
consequently for the more prominent effects observed when
given equivalent doses.

 Simultaneously, since CYP2D6 activities have been

demonstrated to correlate significantly with the
biotransformation of haloperidol.
 TRICYCLIC ANTIDEPRESSANTS (TCAS)

 In contrast to neuroleptics, studies of ethnic differences in the

pharmacokinetics of the TCAs have led to inconclusive results.

 LITHIUM
 Several recent cross-national comparison studies have
replicated earlier reports from Japanese researchers regarding
the need for lower doses of lithium as well as lower
therapeutic lithium levels among Asians (Lin et al., 1993).

 Due to pharmacodynamics reasons and increased CNS

responsivity.
CULTURE, PERSONALITY TRAITS AND DRUG RESPONSE

 As compared to those imbued with a culture giving strong

emphasis to independence, struggle and action, patients with
cultural backgrounds emphasizing interdependence and
social adaptation would require less medication in general.

 Those who responded in an orthodox manner (i.e., with

sedation) tended to be passive and intellectually oriented,
whereas those who experienced paradoxical reactions to
these drugs were typically action oriented and athletically
inclined.
 Their responses were often characterized by a paradoxical
increase in agitation, tension and anxiety, leading to a need
for higher doses of the medication.
INFLUENCE OF STRESS AND SOCIAL SUPPORT ON DRUG
RESPONSE
 Culture strongly influences the type and level of stress, as well as the
structure and function of social networks.

 Stress and social support are both thought to be important factors affecting
the prognosis and outcome of treatment of the mentally ill.

 People with a higher level of stress and lower degree of social support are
much more likely to become mentally ill, less likely to be compliant with
prescribed medication), and have poorer clinical outcome .

 In addition, alterations in the level of stress and the availability of social

support may also change the therapeutic dosages and therapeutic
concentration ranges of different psychotropics.
 .
 Bipolar patients experienced relapses despite adequate
lithium treatment while subjected to intense interpersonal
conflicts. These episodes were brought under control only
when lithium dosage and concentrations were raised beyond
the ranges previously found adequate.

 The quality of the interaction between network members may

also vary cross-culturally. For example, limited research data
have suggested that American Anglo families are more likely
to be rated with high expressed emotion (EE) as compared to
their British counterparts and Hispanic families tend to have
significantly lower EE ratings as compared to Anglo
Americans and the British.
 Several well-designed studies examining the effect of
expressed emotion have found that patients with high EE
family members (characterized by frequent criticism, hostility,
and emotional over-involvement) were significantly more
likely to relapse on standard neuroleptic doses, and to be
subsequently treated with higher doses of the same
medication.

 It is possible that such cultural differences in family

atmosphere may have important influences on drug
responsiveness across cultures.
CULTURAL INFLUENCE ON PRESCRIPTION PATTERNS

 Wide cross-national variability exists in terms of the type and

dosage of medications used for the treatment of similar conditions.

 Although pharmacokinetic and pharmacodynamics factors may play

a role, more often these differences reflect cross-cultural
differences in beliefs and expectations of both patients and
physicians regarding the clinical and untoward effects of the
medications.

 Cultural stereotypes and biases could also profoundly influence

patterns of prescription.
 This is most clearly demonstrated in a series of studies
consistently demonstrating that African-American patients
are not only far more likely than Caucasian patients to be
assigned a more severe diagnosis such as schizophrenia, but
also to be treated with neuroleptics irrespective of
diagnosis.

 Given the same diagnosis, African-Americans are

significantly more likely to be placed on depot rather than
oral medications, presumably reflecting the clinicians’
heightened concern with problems of compliance.
USE OF TRADITIONAL AND ALTERNATIVE HEALING
METHODS

 Throughout the world, as well as across all ethnic groups in

the United States, traditional herbal medicines continue to
be extensively utilized often side-by-side with modern
Western pharmaceutical agents.

 Contrary to the beliefs of most physicians, many of these

herbal drugs are pharmacologically active, and capable of
significant interactions with prescribed drugs, both
pharmacokinetically and pharmacodynamically
 For example, the anticholinergic properties inherent in the
Japanese herb Swertia japonica and kamikihi-to and the
Cuban folk medicine Datura candida may cause atropine
psychosis, particularly when ingested concomitantly with
TCAs or low potency neuroleptics.

 Because of its high concentration of caffeine, the South

American holly, Ilexguayusa can counteract the sedative and
anxiolytic effects of benzodiazepines and related
compounds.
 Concurrent use of the Nigerian root extract of
Schumanniophyton problematicum, a popular treatment for
psychosis among Nigerians with sedative hypnotics or
neuroleptics may lead to potentiation of tranquilizing
effects.

 Several Chinese herbs, including Fructus Schizandrae,

Corydalis bungeane Diels, Kopsia officinallis, Clausena
lansium, muscone, ginseng, and glycyrrhiza, have been
found to have potent stimulating effects on the cytochrome
P-450 enzymes, and oleanolic acid contained in Sertia
mileensis and ligustrum lucidium Ait substantially inhibit
the activities of these enzymes
COMPLIANCE ISSUES

 Non-compliance is a major problem in the treatment of

chronic medical conditions. Most psychopharmacotherapies
require long-term treatment, and are often plagued by a
significant degree of poor compliance. In addition, several
recent studies have found that compliance to psychotropics
may be more problematic among non-Western populations.

 Divergence in the beliefs between patients and clinicians and

communication difficulties have been regarded as the major
reasons of such ethnic differences in compliance.
PLACEBO EFFECTS

 The placebo effect is commonly regarded as being

responsible for 30%-70% of the therapeutic responses
observed in clinical settings.

 wide variety of factors may significantly influence the extent

of placebo responses, including diagnosis, color, size,
preparation, and method of drug administration
 Since placebo effects are mediated through; rather than
mechanisms, they are expected to be largely influenced by
culture.

 Ethnic differences in propensity to report side effects have

also been regarded as possibly caused by placebo effects.

 For example, Lee (1993) reported untoward symptoms

attributed to lithium by a group of Hong Kong Chinese
patients treated with lithium. In contrast to Western
patients, Chinese rarely complained of missing of highs, loss
of creativity weight gain and metallic taste.
 Although polydipsia and polyuria were present in the majority
of these patients, these side effects were positively, not
negatively, interpreted.

 Complaints such as lethargy, poor memory and drowsiness,

appeared to be related to their fear of not being able to work,
and actually occurred at a similar frequency as age and sex
matched normal controls.
SUMMARY AND CONCLUSIONS

 Ethnicity and culture are important variables that

significantly influence the effect of psychotropics.

 Mechanisms responsible for such differences include not only

those belonging to the realm of pharmacokinetics and
pharmacodynamics, but also various psychosocial factors.
 Clinically, the importance of culture and ethnicity in health
care has been accentuated by the rapid diversification of
the population in all metropolitan areas of the world.

 With large-scale population shifts and the rapid pace of

intercontinental transportation and migration, most
psychiatrists can no longer limit their practice to culturally
or ethnically homogenous clienteles.

 Patients’ divergent beliefs, expectations, dietary practices,

and genetic constitution must be taken into consideration
in psychopharmacotherapy.
 Ethnic and cultural considerations also are important for
drug development.

 The safety and efficacy of pharmaceutical agents are usually

tested only in selected groups (in this country, most often
young white males).

 The resulting parameters are then widely applied to other

populations with unknown safety and efficacy.
 Furthermore, with the escalating cost of drug development
and marketing, international collaboration becomes
increasingly important.

 In order for pharmacokinetic and clinical trial results to be

shared internationally, potential ethnic and cultural
influences must be identified.

 Failure to do so may lead to the inappropriate application of

findings derived from one population to another, with
unforeseen and potentially disastrous results.
REFERENCES

 Psychopharmacology, Ethnicity and Culture KEH-MING LIN,

RUSSELL E. POLAND & DORA ANDERSON.

 Ethnic and cultural factors in psychopharmacology Dinesh

Bhugra & Kamaldeep Bhui.
THANK YOU