Ethnopsychopharmacology

David C. Henderson, M.D.

Massachusetts General Hospital Harvard Medical School

Disclosure

 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 Psychopharmacology I



Misdiagnosis

 Bipolar Disorder and Psychotic Depression 

Mistrust of the health care system

 Seek attention at later stage of psych. episode 

Cultural beliefs and expectations

 Perception of illness and its treatment 

Clinicians do not explain psychotropic medications to patients, addictiveness

Non-biological Issues Affecting Psychopharmacology II

 Traditional and Alternative Healing  Herbal medicines, Traditional healers...

 Compliance  Social Supports System  Language Issues  Communication Styles  Physicians’ and Health care System biases (rates of involuntary commitment, seclusion, restraint, dosing, depots)

Compliance Affected By:

 Medication side effects,  Polypharmacy  Incorrect dosing  Poor therapeutic alliance  Lack of community support, shame  Lack of money or transportation or access to care/meds  Substance Abuse  Concern about the addictiveness of meds.

Factors Determining Pharmacological Response Other factors Culture Environmental factors Ethnicity Genetics

Pharmacokinetics

Dosage Side effects

Pharmacodynamics

Clinical response

Gender Differences

 Differences in diet  Oral contraceptives  Hormonal fluctuations  3A4   24% Increased liver activity in women 45% increased gut activity in women  1A2   Little differences However, substrates (clozapine, olanzapine, fluvoxamine, tacrine) higher concentrations in women

CYP2D6 Substrates      Antipsychotics haloperidol*, reduced haloperidol, perphenazine, phenothiazines*, thioridazine*, olanzapine*, risperidone*, sertindole* Antidepressants amytrptiline*, desipramine, imipramine*, nortryptiline, trazadone, fluoxetine, paroxetine, venlafaxine Cardiovascular Agents flecanide, propanalol*, metropolol, timolol encanide, Opiates - codeine*, dextramethorphan, hydrocodone* galanthamine

CYP2D6 Metabolic Rates Metabolic type

Rate of metabolism

PM

Poor metabolizer No metabolism

Plasma Drug levels

Toxic drug levels

Clinical Effects

Side effects

EM

Extensive metabolizer Normal metabolism Normal drug level Normal response

CYP2D6 Metabolic Rates Metabolic type Rate of metabolism Plasma Drug levels Clinical Effects SM

Slow metabolizer Slow metabolism High drug levels Side effects higher dose

SEM

Super extensive metabolizer Super fast metabolism Low or no drug level No response at normal doses

Genetic Admixture in the Caribbean Mestizo European Indian African origen Mexico Guatemala Nicaragua Colombia Cuba Brazil Haiti

0%

37

20%

53 60 59 58 69

40%

100

60%

9 30 20 46 17 41 5 9 14 61

80% 100%

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

80 70 60 Caucasians Asians African African American 50 40 30 20 10 0 Functional Nonfunctional Type of Allele Reduced Bradford LD. Pharmacogenomics. 2002(Mar);3(2):229-243.

CYP2D6 Poor & Slow Metabolizers

40 33 37 34.3

30 % 20 10 2.1

0 2.4

7.3

3.1

3.6

4.4

PM SM 2.2

0 1.9

30 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 Americans

 Mexican American: 1% PM; ~18% slow metabolizers  2-10% in various Hispanic groups  The CYP2D6*4, *5, and *6 null alleles along the reduced function alleles *9, *10, and *41 are the major cause for 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 Metabolizers 35 30

29

25 20

19

15

10

10 5

3.5

1 0.8

0 Ethiopeans Saudi Arabians Spainards Europeans Danes Am.

Caucasians

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.

1.6

Ghanaians

0.9

1.2

Malays Colombians

SM’s SEM’s

Percentage of Poor Metabolizers (PM) of CYP2C19

18.5% 20.2% AA (Tennessee) AA (Pennsylvania) Asians Caucasians Hispanic Mexican Am (LA) 3.6% 3.3% 4.8% 4%

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

Diet & The Expression Of Drug Metabolizing Enzymes  CYP3A4   Inhibition by: Grapefruit Juice; Corn Induction by: Flavone; Tangeretin  CYP1A2   Inhibition by: Coffee; Flavone; Quercitin; Corn Induction by: Char-broiled Beef; Broccoli; Cabbage; Carrots; Chili Peppers; High Protein Diet  CYP2D6  Inhibition by: Watercress  CYP2E1  Inhibition: Watercress; Induction: Alcohol; Acetaminophen

Diet Variation, Migration & Acculturation Among Mexican American Women Beans 8.4

15.5

Born in US-ES Born in US-SS Born in Mexico 21.2

6.8

Corn 12.4

33.7

0 5 10 15 20 25 number of times consumed in 1 month 30

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

35 40

Nifedipine Side Effects and Corn 10

Palma-Aguire, 1999

9 8 5 4 7 6 3 2 1 0 S li g ht H A D ro w si en es s D iz zy S le ep y M od era te H A In te ns e H A With Corn Without Corn F ai nt in g F lu sh in g

Clinical Issues/Risks: Antidepressants

 TCA: PM and SM at 2D6 show greater serum level   Asians: may require smaller doses Hispanics: may respond to lower doses and have greater side effects; mixed results   African Americans: respond faster & to lower doses; increased risk of neurotoxicity SSRI’s:   Better Tolerated Risk of inhibiting alternative pathways in PM

SSRI’s: Alonso et al 1997 Hispanics Caucasians 20 18 R e s p o n s e 16 14 12 10 8 6 4 2 0 14.2

12.4

HAMD Response 6 5 e n t P e 4 c r 3 2 1 0 2.2

5.3

Side Effects* * = P< .005

Herb- CYP450 Drug Interactions Drug-A Herbal-B Ciprofloxin Enoxacin Pipemidic acid Fluvoxamine Coffee arabica Llex paullina Yerba mate Theophyline Phenytoin Piper longum Piper nigum P450 1A2 inhibition 1A2 inhibition Licorice Quinidine Haloperidol Moclobemide Nifedipine Seldane, xanax Cyclosporine Digoxin, Indinavir Amitriptyline sparteine in Cytisus scoparius 1A2 induction 2D6 inhibition grapefruit, corn 3A4 inhibition Panax ginseng Ginkgo biloba St. John’s wort Licorice ? Induction Interaction Increased conc. B Caffeine toxicity Increased conc. A Decreased conc. A Increased conc. B Circulatory collapse Increased conc. A Increased effects Decreased conc. A Decreased effects

An Ethnopsychopharmacological Approach  Assessment  Cultural formulation for Diagnosis: Careful elicitation of beliefs, expectations, history of help seeking, nature of the support system, use of “alternative” treatment and healing methods  Choice of Medication   Medical history, concurrent medications, diet, & food supplements/herbs Involve patient and family in treatment decisions  Monitor Patient    Proceed slowly - Involve family If side effects intolerable - lower dosages, or chose drug metabolized through different route If no response-check compliance, raise dose and monitor levels, add inhibitors, switch drug, augmentation