EthnopsychopharmacologyEthnopsychopharmacology

David C. Henderson, M.D.David C. Henderson, M.D.

Massachusetts General HospitalMassachusetts General Hospital

Harvard Medical SchoolHarvard Medical School

DisclosureDisclosure

Takeda Pharmaceuticals - Research grant

Solvay - Research grant; Honorarium for lecture/consultant: BMS, Janssen, Pfizer Solvay - grant

BMS, Janssen, Pfizer, Solvay - honorarium for lectures/consultant

Massachusetts General Hospital Psychiatry Academy - Presenter. (The educational programs conducted by the MGH Psychiatry Academy are supported through Independent Medical Education (IME) grants from various pharmaceutical companies.)

Non-biological Issues Affecting Non-biological Issues Affecting Psychopharmacology IPsychopharmacology I

MisdiagnosisMisdiagnosis Bipolar Disorder and Psychotic DepressionBipolar Disorder and Psychotic Depression

Mistrust of the health care systemMistrust of the health care system Seek attention at later stage of psych. episodeSeek attention at later stage of psych. episode

Cultural beliefs and expectationsCultural beliefs and expectations Perception of illness and its treatmentPerception of illness and its treatment

Clinicians do not explain psychotropic medications Clinicians do not explain psychotropic medications to patients, addictivenessto patients, addictiveness

Non-biological Issues Affecting Non-biological Issues Affecting Psychopharmacology IIPsychopharmacology II

Traditional and Alternative HealingTraditional and Alternative Healing Herbal medicines, Traditional healers...Herbal medicines, Traditional healers...

ComplianceCompliance

Social Supports SystemSocial Supports System

Language IssuesLanguage Issues

Communication StylesCommunication Styles

Physicians’ and Health care System biases (rates of Physicians’ and Health care System biases (rates of involuntary commitment, seclusion, restraint, dosing, involuntary commitment, seclusion, restraint, dosing, depots)depots)

Compliance Affected By:Compliance Affected By:

Medication side effects, Medication side effects,

PolypharmacyPolypharmacy

Incorrect dosingIncorrect dosing

Poor therapeutic alliancePoor therapeutic alliance

Lack of community support, shameLack of community support, shame

Lack of money or transportation or access to care/medsLack of money or transportation or access to care/meds

Substance AbuseSubstance Abuse

Concern about the addictiveness of meds.Concern about the addictiveness of meds.

Factors Determining Factors Determining Pharmacological ResponsePharmacological Response

Pharmacokinetics Pharmacodynamics

DosageSide effects

Clinical response

GeneticsEnvironmental factors

Culture EthnicityOther factors

Gender DifferencesGender Differences

Differences in dietDifferences in diet

Oral contraceptivesOral contraceptives

Hormonal fluctuationsHormonal fluctuations

3A43A4 24% Increased liver activity in women24% Increased liver activity in women 45% increased gut activity in women45% increased gut activity in women

1A21A2 Little differencesLittle differences However, substrates (clozapine, olanzapine, fluvoxamine, However, substrates (clozapine, olanzapine, fluvoxamine,

tacrine) higher concentrations in womentacrine) higher concentrations in women

CYP2D6 SubstratesCYP2D6 Substrates AntipsychoticsAntipsychotics--

haloperidol*, reduced haloperidol, perphenazine, phenothiazines*, haloperidol*, reduced haloperidol, perphenazine, phenothiazines*, thioridazine*, olanzapine*, risperidone*, sertindole*thioridazine*, olanzapine*, risperidone*, sertindole*

AntidepressantsAntidepressants--amytrptiline*, desipramine, imipramine*, nortryptiline, trazadone, amytrptiline*, desipramine, imipramine*, nortryptiline, trazadone, fluoxetine, paroxetine, venlafaxinefluoxetine, paroxetine, venlafaxine

Cardiovascular AgentsCardiovascular Agents- encanide, - encanide, flecanide, propanalol*, metropolol, timolol flecanide, propanalol*, metropolol, timolol

OpiatesOpiates- codeine*, dextramethorphan, hydrocodone*- codeine*, dextramethorphan, hydrocodone* galanthaminegalanthamine

CYP2D6 Metabolic RatesCYP2D6 Metabolic Rates

Poor metabolizer

PM No

metabolismToxic drug

levelsSide

effects

EMExtensive metabolizer

Normal metabolis

m

Normal drug level

Normal response

Metabolic type

Rate of metabolism

Plasma Drug levels

Clinical Effects

CYP2D6 Metabolic RatesCYP2D6 Metabolic Rates

Slow metabolizer

SM Slow

metabolism

High drug levels

Side effect

s-higher dose

Super extensive metabolizer

Super fast metabolis

m

Low or no drug level

No response at

normal doses

Metabolic type

Rate of metabolism

Plasma Drug levels

Clinical Effects

SEM

Genetic Admixture in the CaribbeanGenetic Admixture in the Caribbean

100

37 61

53 46

58 20 14

69 17 5 9

59 41

60 9 30

0% 20% 40% 60% 80% 100%

Haiti

Brazil

Cuba

Colombia

Nicaragua

Guatemala

Mexico

Mestizo European Indian African origen

80

70

60

50

40

30

20

10

0

Caucasians

Asians

African

African American

Functional NonfunctionalType of Allele

Reduced

CYP2D6 Allele Frequency in European Caucasians, Asians, African CYP2D6 Allele Frequency in European Caucasians, Asians, African Americans and AfricansAmericans and Africans

Bradford LD. Pharmacogenomics. 2002(Mar);3(2):229-243.

CYP2D6 Poor & Slow MetabolizersCYP2D6 Poor & Slow Metabolizers

1.9

34.3

30

02.22.1 2.4

7.3

3.1 3.64.4

3733

0

10

20

30

40

Africa

n Ameri

can

Asian

Cauca

sian

Mexica

n Ameri

can

Nicarag

uans

Ngawbe

Embera

Cuna/Map

uche

Tanza

nians

%

PM SM

Mendoza et al. Clin Pharmacol Ther. 2001; 70:552-560; Leathart et al. Pharmacogenetics. 1998; 8:529-541; Masimirembwa and Hassler, In Pharmacogenetics of Drug Metabolizing Enzymes in Black African Population. Edited by Masimirembwa, 1997; p1-21, Stockholm, Kongl; Dahl et al. Pharmacogenetics. 1995; 5:159-164.

Mexican AmericansMexican Americans

Mexican American: 1% PM; ~18% slow metabolizersMexican American: 1% PM; ~18% slow metabolizers 2-10% in various Hispanic groups2-10% in various Hispanic groups

The CYP2D6*4, *5, and *6 null alleles along the reduced The CYP2D6*4, *5, and *6 null alleles along the reduced function alleles *9, *10, and *41 are the major cause for function alleles *9, *10, and *41 are the major cause for diminished 2D6 activity in Mexican Americans.diminished 2D6 activity in Mexican Americans.

Luo et al. Eur J Clin Pharmacol. 2005 Dec;61(11):797-802

Agundez et al. Pharmacogenetics. 1997 Aug;7(4):337-40.

CYP2D6 Super Extensive MetabolizersCYP2D6 Super Extensive Metabolizers

29

19

10

1 0.83.5

1.6 0.9 1.2

0

5

10

15

20

25

30

35

Ethiopeans SaudiArabians

Spainards Europeans Danes Am.Caucasians

Ghanaians Malays Colombians

Perc

ent w

ith C

YP2

D6*

2XN

McLellan et al. Pharmacogenetics. 1997; 7:187-191.Agundez et al. Clin Pharmacol Ther. 1995; 57:265-269.Aklillu et al. J Pharmacol Exp Ther. 1996; 278:441-446.

SM’s

SEM’s

Percentage of Poor Metabolizers (PM) of CYP2C19

3.6%

18.5%

3.3%

4.8%4%

20.2%

AA (Tennessee)

AA (Pennsylvania)

Asians

Caucasians

Hispanic

Mexican Am (LA)

Daniel HI, Edeki TI. Psychopharmacol Bull. 1996; 32: 219-230.

Diet & The Expression Of Drug Metabolizing EnzymesDiet & The Expression Of Drug Metabolizing Enzymes

CYP3A4CYP3A4 Inhibition by: Grapefruit Juice; CornInhibition by: Grapefruit Juice; Corn Induction by: Flavone; TangeretinInduction by: Flavone; Tangeretin

CYP1A2CYP1A2 Inhibition by: Coffee; Flavone; Quercitin; CornInhibition by: Coffee; Flavone; Quercitin; Corn Induction by: Char-broiled Beef; Broccoli; Cabbage; Carrots; Chili Induction by: Char-broiled Beef; Broccoli; Cabbage; Carrots; Chili

Peppers; High Protein DietPeppers; High Protein Diet

CYP2D6CYP2D6 Inhibition by: WatercressInhibition by: Watercress

CYP2E1CYP2E1 Inhibition: Watercress; Induction: Alcohol; AcetaminophenInhibition: Watercress; Induction: Alcohol; Acetaminophen

Diet Variation, Migration & Acculturation Among Diet Variation, Migration & Acculturation Among Mexican American WomenMexican American Women

15.5

21.2

33.7

12.4

8.4

6.8

0 5 10 15 20 25 30 35 40

Corn

Beans

number of times consumed in 1 month

Born in US-ES

Born in US-SS

Born in Mexico

Dixon et al. Am Jou Epidemiology. 2000;152:548-57

Nifedipine Side Effects and CornNifedipine Side Effects and Corn

0

1

2

3

4

5

6

7

8

9

10Fr

eque

ncy

Slig

ht H

AD

row

sien

ess

Diz

zy

Slee

pyM

oder

ate

HA

Inte

nse

HA

Fain

ting

Flus

hing

With CornWithout Corn

Palma-Aguire, 1999

Clinical Issues/Risks: AntidepressantsClinical Issues/Risks: Antidepressants

TCA: PM and SM at 2D6 show greater serum levelTCA: PM and SM at 2D6 show greater serum level Asians: may require smaller dosesAsians: may require smaller doses Hispanics: may respond to lower doses and have greater side Hispanics: may respond to lower doses and have greater side

effects; mixed resultseffects; mixed results African Americans: respond faster & to lower doses; increased African Americans: respond faster & to lower doses; increased

risk of neurotoxicityrisk of neurotoxicity

SSRI’s: SSRI’s: Better ToleratedBetter Tolerated Risk of inhibiting alternative pathways in PMRisk of inhibiting alternative pathways in PM

SSRI’s: Alonso et al 1997SSRI’s: Alonso et al 1997

14.2

12.4

0

2

4

6

8

10

12

14

16

18

20

HAMD Response

Response

HispanicsCaucasians

2.2

5.3

0

1

2

3

4

5

6

Side Effects*

Percent

* = P< .005

Herb- CYP450 Drug InteractionsHerb- CYP450 Drug InteractionsDrug-A Herbal-B Drug-A Herbal-B P450 P450 Interaction InteractionCiprofloxinCiprofloxin Coffee arabicaCoffee arabica 1A2 inhibition 1A2 inhibitionEnoxacinEnoxacin Llex paullinaLlex paullina Increased conc. B Increased conc. BPipemidic acidPipemidic acid Yerba mateYerba mate Caffeine toxicity Caffeine toxicityFluvoxamineFluvoxamine

TheophylineTheophyline Piper longumPiper longumPhenytoinPhenytoin Piper nigumPiper nigum 1A2 inhibition 1A2 inhibition Increased conc. A Increased conc. A

LicoriceLicorice 1A2 induction1A2 induction Decreased conc. A Decreased conc. A

QuinidineQuinidine sparteine insparteine in 2D6 inhibition 2D6 inhibitionHaloperidolHaloperidol Cytisus scopariusCytisus scoparius Increased conc. B Increased conc. BMoclobemideMoclobemide Circulatory collapse Circulatory collapse

NifedipineNifedipine grapefruit, corn 3A4 inhibitiongrapefruit, corn 3A4 inhibitionSeldane, xanaxSeldane, xanax Panax ginsengPanax ginseng Increased conc. A Increased conc. A

Ginkgo bilobaGinkgo biloba Increased effects Increased effects

CyclosporineCyclosporine St. John’s wortSt. John’s wort ? Induction? Induction

Digoxin, IndinavirDigoxin, Indinavir Licorice Licorice Decreased conc. A Decreased conc. AAmitriptylineAmitriptyline Decreased effects Decreased effects

An Ethnopsychopharmacological ApproachAn Ethnopsychopharmacological Approach

Assessment Assessment Cultural formulation for Diagnosis: Careful elicitation of beliefs, expectations, Cultural formulation for Diagnosis: Careful elicitation of beliefs, expectations,

history of help-seeking, nature of the support system, use of “alternative” history of help-seeking, nature of the support system, use of “alternative” treatment and healing methodstreatment and healing methods

Choice of MedicationChoice of Medication Medical history, concurrent medications, diet, & food Medical history, concurrent medications, diet, & food

supplements/herbssupplements/herbs Involve patient and family in treatment decisionsInvolve patient and family in treatment decisions

Monitor PatientMonitor Patient Proceed slowly - Involve familyProceed slowly - Involve family If side effects intolerable - lower dosages, or chose drug metabolized If side effects intolerable - lower dosages, or chose drug metabolized

through different routethrough different route If no response-check compliance, raise dose and monitor levels, add If no response-check compliance, raise dose and monitor levels, add

inhibitors, switch drug, augmentationinhibitors, switch drug, augmentation