Biological

Vulnerability to

Drug Abuse

DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration
Biological Vulnerability

to Drug Abuse

Editors:

Roy W. Pickens, Ph.D.

Division of Clinical Research

National Institute on Drug Abuse

Dace S. Svikis, B.A.

The Johns Hopkins University School of Medicine

Baltimore, Maryland

NIDA Research Monograph 89

1988

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, Maryland 20857
NIDA Research Monographs are prepared by the research divisions of the

National Institute on Drug Abuse and published by its Office of Science. The

primary objective of the series is to provide critical reviews of research problem

areas and techniques, the content of state-of-the-art conferences, and

integrative research reviews. Its dual publication emphasis is rapid and targeted

dissemination to the scientific and professional community.

Editorial Advisors

MARTIN W. ADLER, Ph.D.

Temple University School of Medicine

Philadelphia, Pennsylvania

SYDNEY ARCHER, Ph.D.

Rensselaer Polytechnic lnstitute

Troy, New York

RICHARD E. BELLEVILLE, Ph.D.

NB Associates,Health Sciences

Rockville, Maryland

KARST J. BESTEMAN

Alcohol and Drug Problems Association

of North America

Washington, D. C.

GILBERT J. BOTVIN, Ph.D.

Cornell University Medical Collage

New York, New York

JOSEPH V. BRADY, Ph.D.

The Johns Hopkins University School of

Medicine

Baltimore, Maryland

THEODORE J CICERO, Ph.D.

Washington University School of

Medicine

St. Louis, Missouri

MARY L. JACOBSON

National Federation of Parents for

Drug-Free Youth

Omaha, Nebraska

REESE T. JONES, M.D.

Langley Porter Neuropsychiatric lnstitute

San Francisco, California

DENISE KANDEL, Ph.D.

College of Physicians and Surgeons of

Columbia University

New York, New York

HERBERT KLEBER, M.D.

Yale University School of Medicine

New Haven, Connecticut

RICHARD RUSSO

New Jersey State Department of Health

Trenton, New Jersey

NIDA Research Monograph Series

CHARLES R. SCHUSTER, Ph.D.

Director, NIDA

THEODORE M. PINKERT, M.D.. J.D.

Acting Associate Director for Science, NIDA

Parklawn Building, 5600 Fishers Lane, RockviIle, Maryland 20857
Biological Vulnerability

to Drug Abuse
ACKNOWLEDGMENT

This monograph is based on papers and discussions from a technical

review on biological vulnerability to drug abuse held on June 2 and

3, 1986, at Rockville, Maryland. The review meeting was sponsored

by the Office of Science and the Division of Clinical Research,

National Institute on Drug Abuse.

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from

the copyright holders to reproduce certain previously published

material as noted in the text. Further reproduction of this

copyrighted material is permitted only as part of a reprinting of

the entire publication or chapter. For any other use, the copyright

holder's permission is required. All other material in this volume

except quoted passages from copyrighted sources is in the public

domain and may be used or reproduced without permission from the

Institute or the authors. Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do

not necessarily reflect the opinions or official policy of the

National Institute on Drug Abuse or any other part of the U.S.

Department of Health and Human Services.

The U. S. Government does not endorse or favor any specific

commercial product or company. Trade, proprietary, or company names

appearing in this publication are used only because they are

considered essential in the context of the studies reported herein.

DHHS Publication No. (ADM)90-1590

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1988, Reprinted 1990

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index

Biosciences Information Service, Chemical Abstracts, Current

Contents, Psychological Abstracts, and Psychopharmacology Abstracts.

iv
Preface

Surveys have shown a heterogeneous pattern of illicit drug use by

the American public. Fortunately, many people never experiment

with illicit drugs and, therefore, avoid the personal tragedy that

drug abuse can bring. Others may be enticed into experimenting

with drugs but, having done so, refrain from any further drug use.

Still others, however, who begin with experimentation, eventually

develop a regular pattern of drug use that is difficult to terminate although it may produce severe personal, social, and medical

complications. The factors that account for these individual

differences in outcome to drug use are largely unknown. They undoubtedly will include a wide range of behavioral, biological,

psychosocial, and cultural influences. In addition, the combination of factors that account for drug experimentation may be different from the combination of factors that account for chronic

drug abuse/dependence. It is important to understand the factors

involved in the etiology of drug abuse for several reasons. Not

only will this knowledge expand our scientific knowledge base, but

it will hopefully lead to improved strategies for the treatment and

prevention of drug abuse as well.

Research findings suggest that genetic factors are involved in the

etiology of alcoholism. It is expected that genetic factors may

also be involved in the etiology of drug abuse. In an attempt to

understand the role of genetic factors in drug abuse, a technical

review on "Biological Vulnerability to Drug Abuse" was held on

June 2-3, 1986, in Rockville, MD. Researchers from the fields of

alcoholism and drug abuse were invited to review the present state

of knowledge in the area and to discuss future research directions.

This research monograph is based in large part on the proceedings

of that review. Included are discussions of strategies for identifying genetic factors in drug abuse, assumptions and methodological

issues that underlie each strategy, results of recent investigations in the area, and implications of the findings for treatment

and prevention of drug abuse. The technical review and resulting

research monograph are intended to stimulate research interest in

v
the genetics of drug abuse, as well as in other factors that may be

involved in the etiology of drug abuse.

Charles R. Schuster, Ph.D.

Director

National Institute on Drug Abuse

vi
Contents

Page

Genetic Vulnerability to Drug Abuse

Roy W. Pickens and Dace S. Svikis. . . . . . . . . . . . . . 1

Influence of Genetic Factors on Drug-Reinforced Behavior

in Animals

Richard A. Meisch and Frank R. George. . . . . . . . . . . . 9

Family Pedigree Studies of Biological Vulnerability to

Drug Dependence

James R. Stabenau. . . . . . . . . . , . . . . . . . . . . 25

The Twin Method in the Study of Vulnerability to

Drug Abuse

Roy W. Pickens and Dace S. Svikis. . . . . . . . . . . . . 41

Etiologic Factors in Substance Abuse: An Adoption

Study Perspective

C. Robert Cloninger. . . . . . . . . . . . . . . . . . . . 52

The High-Risk Paradigm in Alcohol and Drug

Abuse Research

Ralph E. Tarter. . . . . . . . . . . . . . . . . . . . . . 73

Personality Factors in Drug Addiction

James N. Butcher . . . . . . . . . . . . . . . . . . . . . 87

Individual Differences in Drug Response

James R. Wilson. . . . . . . . . . . . . . . . . . . . . . 93

The Role of Psychopathology in the Familial Transmission

of Drug Abuse

Bruce J. Rounsaville . . . . . . . . . . . . . . . . . . . 108

vii
Page

Methodological Issues in Family, Adoption, and

Twin Research

Dace S. Svikis and Roy W. Pickens. . . . . . . . . . . . . 120

Analytical Approaches to Twin and Family Data

Matt McGue . . . . . . . . . . . . . . . . . . . . . . . . 134

Exploring Drug Abuse With Genetic Strategies:

Cautionary Tales

Irving I. Gottesman. . . . . . . . . . . . . . . . . . . . 150

Biological Vulnerability: Treatment Implications/Applications

George E. Bigelow, Robert K. Brooner, Mary E. McCaul,

and Dace S. Svikis . . . . . . . . . . . . . . . . . . . . 165

The Applications of Biological Vulnerability Research to

Drug Abuse Prevention

Edward Kaufman . . . . . . . . . . . . . . . . . . . . . . 174

List of NIDA Research Monographs . . . . . . . . . . . . . . . 181

viii
Genetic Vulnerability to Drug Abuse

Roy W. Pickens and Dace S. Svikis

INTRODUCTION

The purpose of this review is to assess the current status of our

knowledge regarding genetic factors in drug abuse. That genetic

factors may be involved in drug abuse is suggested by several

decades of research in the field of alcoholism, where research has

strongly implicated a role for genetic factors in the etiology of

the disorder. For example, animals can be selectively bred to show

alcohol-accepting characteristics (Deitrich and Spuhler 1984).

Human family studies have shown that first-degree relatives of

alcoholics are more likely to be alcoholic than first-degree relatives of nonalcoholics (Cotton 1979). Adoption studies have found

that adopted-away children of alcoholic parents are more likely to

develop alcoholism than adopted-away children of nonalcoholic

parents (Goodwin et al. 1973). Twin studies have found that

monozygotic twins are more likely to be concordant for alcoholism

than dizygotic twins (Kaij 1960). Finally, high-risk studies have

shown that children of alcoholics differ from children of nonalcoholics in response to alcohol (Schuckit 1985).

In contrast to alcoholism, little is known about genetic factors

that contribute to other types of drug abuse (e.g., heroin addiction and cocaine abuse). In terms of etiology, most attention in

the drug abuse field has been focused on psychosocial factors that

contribute to drug experimentation by adolescents (Jones and

Battjes 1985). Only limited attention has been paid to the role of

genetic and environmental factors in drug abuse, particularly as it

relates to the development of compulsive patterns of drug abuse

and/or drug dependence. Evidence suggests that the pattern of

inheritance for drug abuse may be similar to that for alcoholism.

Drug abusers frequently abuse alcohol, and alcoholics often report

problematic drug use (Barr and Cohen 1987; Benzer and Cushman 1982;

Croughlin et al. 1981). Also, alcoholism and drug abuse tend to

run in the same families. Family studies of alcoholism have found

increased rates of pyschiatric disorders (including drug abuse) in

the relaties of alcoholics (Meyer 1986). High rates of alcoholism

1
have also been found among the relatives of drug abusers (Smith et

al. 1966; Ellinwood et al. 1966).

One reason for the paucity of genetic studies in drug abuse has

been the difficulty of obtaining a sufficient number of subjects

for research purposes. Compared to alcoholism, drug addiction

occurs less frequently in the general population, and drug abusers

are more difficult to recruit into research because of the illicit

nature of their drug abuse activities. Nevertheless, studies of

the role of genetic factors in drug abuse are important for several

reasons. First, such studies would extend our scientific knowledge

base in the areas of behavioral genetics and behavioral pharmacology. Second, in providing better understanding of the etiology of

substance abuse, these studies would complement studies previously

conducted in the alcoholism area. In fact, knowledge gained from

research with alcoholism should prove useful in directing research

in the drug abuse field. Finally, given the high cost of drug

abuse to our nation and the growing AIDS problem among intravenous

drug abusers, it is essential that we improve our understanding of

basic factors underlying drug abuse so that improved methods of

treatment and prevention of the disorder can be developed.

GENETIC INFLUENCES IN DRUG ABUSE

If genetic factors are involved in drug abuse, what does this mean?

First, we must realize that genes do not directly cause behavior.

No gene or set of genes, for example, will directly cause a person

to become a drug abuser or to engage in drug-taking behavior.

Instead, genes are segments on chromosomes that code for the production of specific proteins (or serve to regulate the activities

of other genes) that are important in the control of behavior. If

a gene is absent, a protein that controls the development or function of a physiological system may not be produced. In certain

cases, the impact may be obvious, as in the case of phenylketonuria, when failure of a gene to code for the enzyme responsible for

metabolism of phenylalanine results in development of a severe form

of mental retardation. In other cases, however, the impact of

genes on behavior may be less obvious but just as real, as when

genetic factors produce a tendency or predisposition to respond in

a certain manner. Such is believed to be the influence of genes on

a number of behavioral traits and disorders, including alcoholism

and drug dependence. Thus, genes are not the sole determinant of

alcoholism or drug dependence, but their presence (or absence) may

increase the likelihood that a person will become alcoholic or drug

dependent.

Second, as the above statement indicates, genes do not act alone in

determining whether a person will become alcoholic or drug dependent. Our experience in behavioral genetics suggests that both

genetic and environmental factors will ultimately be implicated in

the etiology of drug abuse. As with alcoholism, simple cause-andeffect models will not be sufficient for explaining vulnerability.

Rather, various combinations of biological and environmental factors are likely to be identified that function to attenuate or

2
exacerbate an individual's likelihood for becoming drug dependent.

Just because an individual has a genetic tendency for developing

drug dependence does not mean he or she will necessarily develop

the disorder. Whether the disorder develops will ultimately depend

on environmental influences. Certain types of environmental influences are believed to be necessary for a genetically vulnerable

person to develop drug dependence. For example, one environmental

influence that is essential to the development of the disorder is

that an individual must initially engage in drug-taking behavior.

Thus, while a person may be genetically loaded for drug dependence,

if drugs are never used, that person will never run the risk of

becoming drug dependent. The presence of other environmental factors in the development of drug dependence (e.g., drug availability, the manner in which a person uses drugs) is also suspected.

These may include environmental influences that operate within the

immediate milieu (e.g., family and peer influences) or more broadly

(e.g., cultural factors).

Third, genes may influence a person's tendency to develop drug

dependence in many ways. Most people believe that genetic

influences operate by producing an aberrant or idiosyncratic

biological response to drugs. For example, genes may make some

people more (or less) sensitive to a drug's effect, or they may

produce a qualitatively different drug effect in some people than

in others. While this may indeed be the case, it is important to

recognize that there are mechanisms other than pharmacological

mechanisms that may account for genetic effects. One nonpharmacological mechanism is that genes may determine personality characteristics that increase the probability of drug abuse. For

example, a person may inherit a sociopathic personality that increases the likelihood of contact and experimentation with drugs.

Cultural factors may in part be genetically determined, which may

increase the likelihood of drug use that will eventually lead to

increased rates of drug dependence.

For both pharmacological and nonpharmacological factors that

influence drug dependence, it is important to determine the level

at which genetic factors exert their effects. For example, genes

may operate by putting individuals into high-risk situations where

drugs are readily available for use, by increasing the likelihood

that drug use (experimentation) will occur, or by increasing the

probability that initial regular drug use will eventually escalate

into drug dependence.

Fourth, genetic influences should not be viewed solely in terms of

factors that predispose an individual to drug abuse. Instead,

genetic influences can also operate by eliminating factors that

protect an individual from drug abuse. If genes serve to eliminate

or reduce the intensity of adverse drug effects, then factors that

suppress excessive drug use will be removed. This will result in

greater drug use than would have occurred had the natural protective factors been present. For example, in the case of alcoholism,

genetic influences that reduce severity of hangover symptoms may

hypothetically eliminate a mechanism that ordinarily controls

3
excessive alcohol use. As a result, people with reduced hangover

effects from alcohol may engage in more intense drinking behavior,

which will increase the likelihood of developing alcoholism. Similar mechanisms may also operate with other forms of drug abuse.

Finally, if genetic factors are involved in drug abuse, it is

important to determine whether similar or different genetic factors

are involved in alcoholism and drug abuse, as this may guide future

research to enhance our understanding of the physiological processes that underlie both disorders. For example, if different genetic factors are found, this suggests that different physiological

mechanisms may underlie alcoholism and drug abuse. If similar

genetic factors are found, however, this suggests a common mechanism for both types of disorders. If this is the case, then research can focus on physiological or biochemical processes that

are common to both disorders, rather than concentrating on processes that are unique to each disorder. The same is also true for

genetic factors that may be involved in different forms of drug

abuse (e.g., heroin addiction vs. cocaine abuse).

GENETIC RESEARCH STRATEGIES

Five types of research strategies have been employed in the study

of genetic factors in alcoholism and therefore have relevance to

studies of drug abuse. They are: (1) animal selective-breeding

studies, (2) family studies, (3) adoption studies, (4) twin studies, and (5) high-risk studies. The first four of these are employed in establishing whether a genetic influence is involved in

alcoholism. Animal selective-breeding studies have attempted to

develop strains of animals that show a propensity toward alcohol

drinking. The successful breeding of such strains suggests that

genetic factors may be involved in human alcohol use. After such

strains are developed, further studies can be conducted to determine how these animals differ biologically and behaviorally from

animals that do not show this propensity. Additional research is

needed to determine if animals can be selectively bred to show a

greater propensity for drug taking and to determine the extent to

which this characteristic generalizes across drug classes and/or

alcohol.

Family studies in humans attempt to determine if a disorder (such

as drug abuse) runs in families. A familial pattern is indicated

if the disorder occurs more frequently in relatives of affected

individuals than in relatives of nonaffected individuals. While

evidence of familiality fails to distinguish between genetic and

environmental influences, these results are often most useful in

establishing the direction of future genetic research. Failure to

find familiality suggests that genetic factors are not involved in

the etiology of the disorder. While familial patterns of alcohol

use have been well established, more research is needed on familial

patterns of drug use, including the extent to which drug abuse,

alcoholism, and psychopathology co-occur within the same individual

and across family members.

4
In contrast to family studies, adoption and twin studies permit an

estimate of the relative influences of genetic and environmental

factors in the etiology of a disorder. In adoption studies, the

influence of rearing environment can be largely separated from that

of genetics by use of children born of affected biological parents

but adopted out early in life and raised by nonaffected foster

parents. Prevalence of the disorder is determined in this group of

adoptees as adults and compared to that of a control group of

adoptees born of nonaffected biological parents but also raised by

nonalcoholic foster parents. While several adoption studies of

alcoholism have been conducted, only one adoption study of drug

abuse has recently been reported (Cadoret et al. 1986). Because of

the strict adoption confidentiality laws that exist in the United

States, most of this research is expected to be conducted

elsewhere.

Twin studies compare concordance for a disorder in monozygotic and

dizygotic twins. Because monozygotic twins have all common genes,

any difference in monozygotic twin pairs must be due to environmental factors. However, since dizygotic twins have only 50 percent

common genes, any difference in dizygotic twin pairs may be due to

either genetic or environmental influences, or both. By comparing

the concordance for a disorder in monozygotic and dizygotic twins,

the relative influences of genetic and environmental factors in the

etiology of a disorder can be determined. While there have been

several twin studies of quantity and frequency of alcohol drinking,

only three twin studies of alcoholism (or the alcohol dependence

syndrome) have been reported. Except for studies of quantity and

frequency of smoking and coffee drinking, only a limited number of

twin studies of quantity and frequency of other drug use have been

reported. To our knowledge, no twin study of drug dependence has

been reported.

The final strategy, the high-risk paradigm, is employed to determine possible mechanisms that may underlie an obtained genetic

effect. High-risk studies attempt to identify factors that contribute to the etiology of a disorder by comparing individuals at

high risk for later developing a disorder to individuals without

such risk. When a disorder is familially linked, children of affected individuals are known to have a greater risk of developing

the disorder than children of nonaffected individuals. Therefore,

responses of such children may be compared to identify factors that

contribute to development of the disorder. In the case of alcoholism, children of alcoholics are known to be at higher risk for

later developing alcoholism than children of nonalcoholics. In

high-risk studies, these children are frequently compared at early

ages to determine possible differences in behavioral and physiological responses, including their response to alcohol. Since children of alcoholics also have a higher risk for drug abuse than

children of nonalcoholics (Cadoret et al. 1986), children of alcoholics may also be employed in studies to identify factors that

contribute to drug abuse. To our knowledge, however, no high-risk

studies of drug abuse have been reported to date.

5
ORGANIZATION OF THE MONOGRAPH

This monograph reviews research on genetic factors in alcoholism

and drug abuse. The review is conducted for the purpose of better

understanding the possible role of genetic factors in drug abuse

and for stimulating research in the drug abuse field. The first

section is a basic review of the research strategies that have been

employed in determining genetic influences in alcoholism. In each

case, the authors were asked to review the available information

concerning the role of genetic factors in alcoholism and to make

extensions whenever possible to the use of the strategies to study

the genetics of drug abuse. In this section, MEISCH and GEORGE

examine the self-administration of drugs by animals selectively

bred for different responses to alcohol. STABENAU reviews the

family pedigree method as a strategy for examining vulnerability to

alcoholism and drug dependence. PICKENS and SVIKIS describe the

twin study method and summarize preliminary findings from a new

twin study of alcoholism and drug abuse. Finally, CLONINGER

reports the results of adoption studies of alcoholism and discusses

possible biochemical correlates of different types of alcoholism.

The next section examines possible mechanisms for inheritance of a

tendency toward alcoholism or drug abuse. Participants were asked

to review either a strategy for identifying specific characteristics that may predispose an individual to drug abuse or to discuss

some of the frequently posited mechanisms for inheritance of a

biological vulnerability to alcoholism or drug abuse. The use of

the high-risk strategy to identify possible mechanisms in the

inheritance of alcoholism is discussed by TARTER. Personality

factors that may mediate a predisposition to drug abuse are discussed by BUTCHER. WILSON discusses individual differences in

drug response by humans and presents preliminary data from individuals with different degrees of genetic and environmental

similarity. Finally, ROUNSAVILLE discusses the role of psychopathology in the transmission of substance abuse.

The third section concerns methodological issues in biological

vulnerability research. SVIKIS and PICKENS discuss assumptions

underlying family, adoption, and twin studies, as well as methodological issues that must be considered in conducting such research.

Statistical approaches to analyzing twin and family data are

discussed by MCGUE, and special problems in drug abuse research

are reviewed by GOTTESMAN.

The last section is a discussion of the practical implications of

research on biological vulnerability to drug abuse. Implications

for the treatment of drug abuse are discussed by BIGELOW, BROONER,

MCCAUL, and SVIKIS, and implications for the prevention of drug

abuse are considered by KAUFMAN.

6
REFRENCES

Barr, H.C., and Cohen, A. Abusers of alcohol and narcotics: Who

are they? Int J Addict 22:525-541, 1987.

Benzer, D., and Cushman, P., Jr. Marijuana use in alcoholism:

Demographic characteristics and effects on therapy. Adv

Alcohol Subst Abuse 2:53-61, 1982.

Cadoret, R.J.; Troughton, E.; O'Gorman, T.W.; and Heywood, E. An

adoption study of genetic and environmental factors in drug

abuse Arch Gen Psychiatry 43:1131-1136, 1986

Cotton N.S. The familial incidence of alcoholism. J Stud Alcohol

40:89-116; 1979.

Croughlin, J.L.; Miller, J.P.; and Whitman, B.Y. Alcoholism and

alcohol dependence in narcotic addicts: A retrospective study

with five years' follow up. Am J Drug Alcohol Abuse 8:85-95,

1981.

Deitrich, R.A., and Spuhler, K. Genetics of alcoholism and alcohol

actions. In: Smart, R.G.; Cappell, H.D.; Glaser, F.B.; Israel,

Y.; Kalant, H.; Popham, R.E.; Schmidt, W.; and Sellers, E.M.,

eds. Research Advances in Alcohol and Drug Problems. Vol. 8.

New York: Plenum Publishing Corporation, 1984. pp. 47-98.

Ellinwood, E.H., Jr.; Smith, W.G.; and Vaillant, G.E. Narcotic

addiction in males and females: A comparison. Int J Addict

1:33-45, 1966.

Goodwin, D.W.; Schulsinger, F.; Hermansen, L.; Guze, S.B.; and

Winokur, G. Alcohol problems in adoptees raised apart from

alcoholic biological parents. Arch Gen Psychiatry 28:238-243,

1973.

Jones,C.L., and Battjes, R.J. Etiology of Drug Abuse:

Implications for Prevention. National Institute on Drug Abuse

Research Monograph 56 DHHS Pub. No. (ADM) 85-1335.

Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1985.

Kaij, L. Alcoholism in Twins: Studies on the Etiology and

Sequelae of Abuse of Alcohol. Stockholm: Almqvist and Wiksell,

1960.

Meyer, R.E. Psychopathology and Addictive Disorders. New York.

Guilford Press, 1986.

Schuckit, M. Studies of populations at high risk for alcoholism.

J Psychiatr Dev 3:31-63, 1985. 

Smith, W.G.; Ellinwood,E.H. Jr.; and Vaillant, G.E. Narcotic

addicts in the mid-1960s. Public Health Rep 81:403-412, 1966.

AUTHORS

Roy W. Pickens, Ph.D.

Director, Division of Clinical Research

National Institute on Drug Abuse

Parklawn Building, Room 1OA-38

5600 Fishers Lane

Rockville, MD 20857

7
Dace S. Svikis, B.A.

Clinical Services Manager, Alcoholism

Treatment Services D-5-C

Francis Scott Key Medical Center

4940 Eastern Avenue

Baltimore, MD 21224

8
Influence of Genetic Factors on

Drug-Reinforced Behavior in Animals

Richard A. Meisch and Frank R. George

INTRODUCTION

This paper provides an overview of genetic effects on drugreinforced behavior. It is limited to animal studies, and since

the majority of research has focused on one drug, namely ethanol,

much of this review concerns ethanol studies. The influences of

genetic factors on drug-reinforced behavior are considered within

the larger context of pharmacogenetic influences on behavior. The

conclusion of this survey of studies can be anticipated by noting

that genetic factors are important determinants of many effects of

abused drugs including their reinforcing effects.

STRAIN DIFFERENCES IN DRUG EFFECTS

Inbred Strains

There are many reports of inbred strains of rats and mice differing in their acute response to drugs (Broadhurst 1978). One

advantage of these studies is the ability to perform correlations

between behavioral and biochemical variables across strains, and

this use of correlations is a powerful means of testing mechanistic hypotheses. One example is that the locomotor effects of

morphine vary with the strain of mouse studied (Castellano and

Oliverio 1975; Brase et al. 1977; Moskowitz et al. 1985). This

effect has been analyzed in a series of experiments and has been

attributed to differences between strains in stimulation of dopaminergic systems by morphine (Oliverio et al. 1983). Another

example is the variation in analgesic response to opiates among

strains, and this variation is significantly correlated with

differences in mu opiate receptor binding (Reith et al. 1981;

Moskowitz and Goodman 1985). An important general finding from

studies with inbred strains is that the various behavioral and

physiological effects of drugs (e.g., locomotor and analgesic

responses) do not necessarily covary across strains, and the

direction and magnitude of response are dependent on the specific

behavior measured.

9
Selective Breeding

It has been possible to go beyond the simple demonstration of

strain differences in drug effects by showing selective breeding

for certain drug effects. One of the best known examples is that

of the short (SS) and long (LS) sleep mice. Starting from a

genetically heterogeneous stock of mice, McClearn and Kakihana

1973) successfully conducted a bidirectional selective breeding

study. They selectively bred mice for both short and long durations of loss of the righting reflex following an intraperitoneal

injection of ethanol. There was a rapid separation of the two

lines. Other lines of animals have been selectively bred for

differences in ethanol effects, such as the most affected (MA) and

least affected (LA) rat lines (Riley et al. 1976; Riley et al.

1977) and the alcohol-tolerant (AT) and alcohol-nontolerant (ANT)

rats (Eriksson and Rusi 1981). As Crabbe and Belknap (1980) note,

the successful selection for these characters provides ipso facto

evidence for genetic control.

STRAIN DIFFERENCES IN ETHANOL AND DRUG DRINKING

Measurement of Ethanol Drinking

Rat and mouse strains differ in the amount of ethanol they drink.

However, before these findings can be critically discussed, it is

necessary to describe the most commonly used technique for measuring ethanol drinking. This technique is the two bottle choice

procedure, introduced by Richter and Campbell (1940). In this

procedure, two bottles are attached to the side of an animal's

home cage. One bottle is filled with an ethanol solution and the

other, with water. The amount of ethanol solution and water consumed is measured once every 24 hours. This technique and variants on it have been used in hundreds of subsequent studies. The

basic findings suggest that rats and mice prefer dilute solutions

of ethanol to water. Neither intoxication nor physical dependence

are reliably observed, which is not surprising given that the rats

and mice do not consume enough ethanol to maintain high sustained

blood ethanol levels (Cicero 1979; Cicero 1980; Meisch 1977;

Meisch 1981; Meisch 1984; Mello 1976; Myers 1978; Pohorecky 1981).

Many attempts have been made to increase ethanol drinking in rats,

including exposure to different types of stress and injection with

a very broad range of drugs. No consistent progress has emerged

from this research, and often findings reported by one laboratory

have not been replicated in other laboratories. In summary,

little progress has been made in generating high levels of elective ethanol intake.

This lack of progress has been attributed in part to the persistent use of the two bottle choice technique (Cicero 1979). For

example, low levels of intake and preference for only low concentrations may indicate that the behavior is controlled by taste

factors rather than by effects that ethanol produces once it is

absorbed. Moreover, it is not clear that the results from

10
preference studies of ethanol-drinking behavior of rats and mice

are generalizable to the ethanol-drinking behavior of humans.

The two bottle choice technique has also been used in studies of

genetic differences in ethanol drinking. The first study, conducted by Mardones and colleagues (1953), selectively bred rats

for high and low ethanol drinking. Large differences in ethanol

intake are also found among inbred mouse strains (McClearn and

Rodgers 1959; McClearn and Rodgers 1961). Differences in ethanol

drinking among selected lines and inbred strains of rats and mice

are well documented, and a large body of literature exists

(Deitrich and Spuhler 1984).

Although strain differences in ethanol drinking have been examined

in many studies, far fewer studies have been carried out with

other drugs (Crabbe and Belknap 1980). In several of these studies, oral morphine consumption was examined. Rats were selectively bred for high and low morphine solution intake (Nichols and

Hsiao 1967). A difference between high and low drinkers rapidly

emerged, and by the third generation there was a fourfold difference in intake. These differences are not due to a more general

selection for acceptance or rejection of aversive-tasting solutions, since the two lines did not differ in their intake of a

quinine solution. Differences in morphine intake, however, have

also been reported for rats selectively bred for high and low

open-field emotional reactivity and for high and low rates of

avoidance learning (Satinder 1977).

Several studies have been conducted with inbred mouse strains

(Eriksson and Kiianmaa 1971; Horowitz et al. 1977). In one study,

C57BL/6 mice consumed more morphine solution than did CBA mice

(Eriksson and Kiianmaa 1971). In another study, C57BL/6 mice consumed large quantities of a morphine-saccharin solution, whereas

DBA/2 mice consumed little (Horowitz et al. 1977). It is interesting that these findings parallel results with ethanol studies:

C57BL/6 mice display high intakes , and CBA and DBA/2 mice show low

intakes.

Several studies have been conducted with etonitazene, a potent

opioid that is pharmacoloically similar to morphine and is effective when taken by mouth (Wikler et al. 1963). In one experiment,

C57BL/6J and DBA/2J mice were restricted to a 5 μg/ml solution

(George and Meisch 1984). While C57BL/6J mice consumed slightly

more drug solution than water, the DBA/2J mice generally avoided

the drug solution. When both strains were deprived of food and

maintained at reduced body weights, the C57BL/6J mice substantially increased their intake, while the DBA/2J mice decreased their

drug intake. Similar findings were obtained with Wistar and

Sprague-Dawley rats (Carroll et al. 1986). Initially both groups

of rats consumed similar quantities of etonitazene. However, food

deprivation increased the etonitazene intake of Wistar rats but

decreased the drug intake of Sprague-Dawley rats. The decreases

in drug intake during food deprivation are unusual in that food

deprivation usually enhances the reinforcing effects of drugs

11
(Carroll and Meisch 1984). These findings emphasize the degree to

which genotype and environment interact and stress the need to

examine genetically different groups over a range of conditions.

DRUG-REINFORCED BEHAVIOR

Intravenous Drug Self-Administration

In contrast to studies of ethanol drinking, other investigators

have used operant conditioning techniques and concepts to study

drug self-administration. These studies began in 1962 when James

Weeks developed a technique such that animals could intravenously

inject themselves with drugs. Weeks' procedure involved surgically implanting a chronic indwelling venous catheter in rats

(Weeks 1962). The catheter was protected by a harness the rats

wore so that they could not pull out the catheter, and the distal

end of the catheter was connected to an infusion pump. The rats

could inject themselves by pressing a lever, and the lever press

in turn activated electronic equipment that operated the infusion

pump. Using this technique, Weeks reported that rats would inject

themselves with morphine. These findings have been confirmed and

extended in many ways.

Generality of Findings

The fact that animals will self-inject the same drugs that humans

abuse and will not self-inject the drugs that humans do not abuse

has been well established (Griffiths et al. 1980; Johanson and

Balster 1978). Drugs from several pharmacological classes serve

as reinforcers, such as psychomotor stimulants (including nicotine), opioids, dissociative anesthetics, and general depressants

(including ethanol, barbiturates, benzodiazepines, gaseous anesthetics, and some solvents). Drugs also serve as reinforcers when

taken via a number of different routes. For example, drugs serve

as reinforcers when injected intravenously (Young and Herling

1986), intragastrically (Altshuler et al. 1975; Yanagita and

Takahashi 1973), intramuscularly (Goldberg et al. 1976; Katz

1979), and intracerebrally (Goeders and Smith 1983), and when taken orally (Meisch and Carroll, in press) and by inhalation (Wood

et al. 1977; Yanagita et al. 1970). Also, wide species generality

is found (Griffiths et al. 1980). For example, d-amphetamine

functions as a positive reinforcer and is self-injected by baboons

(Griffiths et al. 1976), rhesus monkeys (Balster and Schuster

1973), squirrel monkeys (Goldberg 1973), dogs (Risner 1975). and

rats (Pickens and Harris 1968). However, this wide species generality should not obscure the fact that within species there are

significant differences among animals in their levels of drugreinforced behavior.

Similarities in the Drug-Seeking Behavior of Humans and Other

Animals

Unlike the home cage ethanol studies, a large and consistent body

of data has emerged from studies of drug-reinforced behavior, and

12
there are important similarities between the findings of human

and animal studies. These similarities have been reviewed by

Griffiths et al. (1980) and include comparable functional relationships between independent controlling variables and measures

of drug self-administration. For example, with both humans and

other animals, variables such as type of drug, drug dose, reinforcement schedule, and size of schedule requirement exert

comparable control.

Establishment of Orally Delivered Drugs as Reinforcers

Procedures have been devised to establish orally delivered drugs

as reinforcers (Meisch and Carroll, in press). This line cf research is an outgrowth of the conceptual approach that characterized studies of intravenous drug self-administration. However,

the first drug to be studied using this approach was ethanol

(Meisch and Thompson 1971). To establish orally delivered drugs

as reinforcers, two problems must be overcome: the aversive taste

of most drug solutions and the delay that occurs between drinking

and the onset of the interoceptive effects that follow absorption

(Mello and Mendelson 1971). To overcome these difficulties, several related techniques have been developed. Basically these involve using food-deprived animals and then inducing water drinking

by feeding the animals during the experimental session. Once a

stable pattern of water drinking is established, a dilute solution

of ethanol (or some other drug) is substituted for the water.

Across sessions, the concentration of ethanol is slowly increased. When an intermediate concentration such as 8 percent

(weight/volume (w/v)) is reached, food is no longer given during

the experimental session but is given after the session is over.

Under these conditions, water drinking drops to low levels, but

ethanol drinking persists (Meisch and Thompson 1971; Meisch and

Thompson 1974). These same findings also occur when rhesus

monkeys serve as subjects (Meisch et al. 1975) and when drugs

other than ethanol are tested (Meisch and Carroll, in press).

EFFECTS OF GENOTYPE ON BEHAVIOR REINFORCED BY ORALLY DELIVERED

DRUGS

In the last several years, these techniques have been used to try

to establish ethanol as a reinforcer for two selected lines of

rats and for several inbred strains of rats and mice (Elmer et al.

1986; Elmer et al., in press a; Elmer et al., in press b; Ritz et

al. 1986; Suzuki et al., submitted for publication). More recently, these techniques have been used in an attempt to establish

etonitazene, a potent opioid, as a reinforcer for inbred rats

(Suzuki et al., unpublished data). A major purpose was to determine whether there are genetic influences on drug-reinforced

behavior.

13
Selectively Bred Lines: The Alcohol-Accepting and the AlcoholNonaccepting Rats

Three sets of studies were conducted. One concerned the establishment of ethanol as a reinforcer for alcohol-accepting (AA) and

alcohol-nonaccepting (ANA) rats. These rats were selectively bred

from an original foundation stock based on high and low ethanol

drinking in a two bottle choice paradigm (Eriksson 1968). A variant of previous procedures was used. These rats were maintained

at 75 percent of their free-feeding weight and were induced to

drink water in the operant chamber by giving them food in their

home cage 60 minutes prior to the start of the session. Their

water bottles were removed when they were given food but were

placed back on their cages after the session. Once a stable pattern of water-reinforced responding was present, they were given a

sequence of increasing ethanol concentrations: 0.5, 1, 2, 4, and

5.7 percent. After behavior was stable at 5.7 percent, the time

of feeding was shifted to after the session.

Figure 1 shows that during the induced drinking phase both the AA

and ANA lines consumed progressively larger amounts of ethanol

(g/kg) as the concentration was increased. At 5.7 percent the AA

rats ingested 1.5 g/kg and had blood ethanol levels of 176 mg%.

The ANA rats consumed 0.9 g/kg and had blood ethanol levels of 116

mg%. When access to food was shifted to after the session, however, responding of the AA rats was maintained by 5.7 percent

ethanol, while the responding of the ANA rats dropped to low levels that were not different from subsequent water control values.

Thus, ethanol came to function as a reinforcer for the AA but not

for the ANA rats. The differential maintenance of responding in

the AA rats relative to the ANA rats was confirmed by subsequent

manipulations where, over blocks of sessions, the rats were given

water, then 5.7 percent ethanol (a second time), and then a final

block of water sessions. Figure 2 shows that in the AA but not in

the ANA rats, ethanol consistently maintained high rates of responding that substantially exceeded water control levels (Ritz et

al. 1986). In a related experiment, the ethanol concentration was

varied between 8 and 32 percent (w/v), and responding by the AA

rats was well maintained at all concentrations (Ritz et al., unpublished data).

Selectively Bred Lines: The Ethanol-Preferring and EthanolNonpreferring Rats

At Indiana University, rats have been selectively bred for ethanol

preference (P line) and for ethanol nonpreference (NP line). In

one experiment, the intragastric self-administration of ethanol

was studied (Waller et al. 1984). Rats from the P line intragastrically self-infused ethanol up to 9.4 g/kg of body weight per

day. When water was substituted for the ethanol solution, responding extinguished but returned to previous levels when ethanol

once again replaced water. Thus, for the rats in the P line,

ethanol appeared to serve as a reinforcer. In contrast, rats in

the NP line self-administered only 0.7 g/kg per day. As the

14
FIGURE 1. Ethanol intake (g/kg) and liquid deliveries as a

function of ethanol concentration for AA (n=8) and

ANA (n=8) rats under food-induced conditions on a

fixed-ratio (FR) 1 reinforcement schedule

NOTE: Each data point represents a group mean for 5 consecutive test days. The

mean blood ethanol level at 5.7 percent for the AA rats was 176±20 mg%

(mean+SEM). and for the ANA rats it was 116±24 mg%.

SOURCE: Ritz et al. 1986, Copyright 1966, Pergamon Journals, Ltd.

15
FIGURE 2. Liquid deliveries on consecutive test days obtained by

AA (n=8) and ANA (n=8) rats as a function of liquid

present : 5.7 percent ethanol or 0 percent ethanol

(water vehicle)

NOTE: Repeated measures ANOVA: Line. F(1,14)=15.42. p<0.002: concentration,

F(3,42)=18.40. p<0.0001; ANA, F(3,21)=1.08. n.s.; AA, F(3,21)=18.14,

p<0.0001. AA Dunnett's t (df=12): 5.7 percent vs. retest=1.71, n.s.;

0 percent vs. retest=0.16, n.s.; 5.7 percent vs. 0 percent=4.15. p<0.01.

one-tailed.

SOURCE: Ritz et al. 1966. Copyright 1986, Pergamon Journals, Ltd.

investigators noted, these findings indicate that the reinforcing

effects of ethanol are postabsorptive and not due to ethanol's

taste or smell.

Studies With Inbred Strains of Rats and Mice

The establishment and maintenance of ethanol-reinforced behavior

has been studied in two inbred rat lines, the Lewis and Fischer

344 rats (Suzuki et al., submitted for publication). These lines

were studied because they have had no common ancestors for at

least 75 years, thereby maximizing their possible genetic divergence. Ethanol was established as a reinforcer using a foodinduced drinking procedure. The rats were maintained at 80

percent of their free-feeding weight. They were then given their

daily food ration in the operant conditioning chamber where they

could obtain small volumes of water by pressing a lever. A stable

pattern of eating followed by water drinking soon developed.

Subsequently a series of increasing ethanol concentrations was

16
substituted for water. After responding stabilized at 5.7 percent, feeding was shifted to the home cage after completion of the

experimental session.

For both the Lewis and Fischer 344 strains, ethanol maintained

higher response rates and was consumed in larger volumes than the

water vehicle. In addition, in both strains blood ethanol levels

increased with increases in ethanol concentration. However, Lewis

rats drank substantially more ethanol than Fischer rats. The

typical inverted U-shaped dose-response function between ethanol

concentration and number of drug deliveries was observed for the

Lewis rats, whereas for the Fischer rats responding did not consistently exceed that for water. For the Lewis strain, as the

fixed-ratio (FR) size was increased, the number of responses increased almost in direct proportion to the FR size, so that at the

lower FR values the rats were obtaining similar numbers of deliveries at different FR sizes. In contrast, for the Fischer strain,

response rate was an inverted U-shaped function of FR size, and

the number of deliveries and blood ethanol levels decreased with

increases in FR size. At FR 16, responding of the Lewis rats was

high, while that of the Fischer rats decreased to low values.

Overall, Lewis rats showed significantly higher values of response

rates, ethanol deliveries, and blood ethanol levels. Ethanolinduced behavioral activation was also observed in Lewis but not

in Fischer rats. These results support the conclusion that ethanol serves as a strong positive reinforcer for Lewis rats and as a

weak positive reinforcer for Fischer rats.

In a third set of experiments, two inbred mouse strains, the

C57BL/6J and the BALB/cJ mice have been studied. As in previous

studies, ethanol drinking was initially induced by maintaining the

mice at a reduced body weight and feeding them one meal a day.

After eating food pellets, the mice reliably drank water. When a

stable pattern of water drinking was established, a series of increasing ethanol concentrations (1, 2, 4, and 8 percent w/v) replaced the water. Mice from both strains drank substantial

amounts of ethanol. At 8 percent ethanol, C57BL/6J mice had blood

levels of 269 mg/dl, and the BALB/cJ mice had blood levels of 183

mg/dl. However, when access to food was switched to after the

session, large differences emerged between the two strains. The

C57BL/6J mice persisted in drinking substantial amounts of ethanol

(2.45 g/kg/30-min session), whereas the BALB/cJ mice drank very

little (0.57 g/kg/30-min session). To document that ethanol was

serving as a reinforcer, water was substituted for ethanol, and

responding by the C57BL/6J mice greatly decreased. When 8 percent

ethanol again replaced water, responding increased to previous

levels. Lever presses by the BALB/cJ mice were much lower in number and were only slightly higher than water values. Thus, ethanol had come to serve as a reinforcer for the C57BL/6J mice but

probably not for the BALB/cJ mice (Elmer et al., in press a).

These findings were systematically replicated in a second experiment where ethanol concentration was varied from 1 to 32 percent.

At 8 and 16 percent w/v, responding by the C57BL/6J mice reliably

17
exceeded water control values, whereas responding by the BALB/cJ

mice never rose above water values. The pattern of responding was

similar to that seen when ethanol serves as a reinforcer for other

species; the highest rate of responding occurred at the beginning

of the session and was negatively accelerated (Elmer et al., in

press b). In a third experiment with C57BL/6J and BALB/cJ mice,

ethanol deliveries occurred under an intermittent schedule of reinforcement, specifically an FR schedule. As the FR value was

increased from 1 to 2 to 4, the rate of responding of the C57BL/6J

mice increased and reliably exceeded water values. In contrast,

responding by the BALB/cJ mice was only marginally maintained

(Elmer et al., in preparation). Thus, ethanol functioned as an

effective reinforcer for the C57BL/6J mice and as a marginal or

ineffective reinforcer for the BALB/cJ mice.

In our studies, differences among strains in the reinforcing efficacy of ethanol parallel differences found in earlier preference

studies of ethanol drinking. This suggests that these two types

of ethanol-drinking behavior share at least some common underlying

mechanisms. However, these mechanisms may be related to preabsorptive rather than postabsorptive factors.

We have shown that genotype has large effects on both the establishment and maintenance of ethanol-reinforced behavior. These

findings have been obtained with inbred strains of rats and mice

as well as with selected lines of rats. Our findings of operant

responding reinforced with orally delivered ethanol complement

results from the study of operant responding reinforced with

intragastrically delivered ethanol (Waller et al. 1984). Taken

together, these studies demonstrate the importance of genotype as

a determinant of ethanol-reinforced behavior.

Etonitazene Intake by Lewis and Fischer 344 Rats

To determine whether genotype also influences the establishment

and maintenance of drug- (other than ethanol) reinforced behavior,

we employed similar procedures to induce drinking of etonitazene

solutions. In brief, food-deprived rats were given their daily

ration of food in the operant conditioning chamber. After eating

the food, the rats drank water. Once a stable pattern of water

drinking was established, a series of increasing etonitazene concentrations was substituted for water. The drug concentration was

gradually increased to 5 μg/ml. At this concentration, the time

and location of feeding were changed. Food was given after the

session and in the home cage. Thus, drinking was no longer induced by feeding. The Lewis rats continued to drink the etonitazene solution, whereas the Fischer rats did not. When the drug

solution was presented under FR schedules of reinforcement, responding by Lewis rats increased with increases in the size of the

schedule. In contrast, Fischer rats displayed very low response

rates. When water was substituted for etonitazene, responding by

the Lewis rats declined, while responding by Fischer rats remained

at low levels. Thus, etonitazene came to serve as a reinforcer

for Lewis but not for Fischer rats (Suzuki et al., unpublished

18
data). These findings differ from the earlier ethanol study,

where ethanol served as a reinforcer for both strains to different

degrees. The results with etonitazene are of interest in that,

apart from studies with ethanol, these are the first findings of

strain differences in drug-reinforced operant behavior.

CONCLUSIONS

Genetic factors are probably important determinants of reinforcing

effects of all abused drugs. The effects of genotype can be large

in magnitude. However, in quantitative terms it is not known precisely how important genetic variables are. Also, the mechanisms

of these effects are not known. It is unlikely, however, that

strain and selected line differences are due solely to acceptance

or rejection of novel tasting substances, since genetic factors

are also important determinants of drug action when drugs are

simply administered to an organism (e.g., intragastrically).

Drug-reinforced behavior is complex in that it is a learned operant behavior that is determined by many variables including the

animal's experimental history, the dose of the drug, deprivational

states, and schedule of reinforcement. This means that there are

many possible points at which strains may differ. For example,

two strains may show identical behavior at a low drug dose but

differences at high doses. Also, strains may have equivalent drug

intakes under an FR 1 schedule but different intakes at higher

ratio values. A third example is that strains may show equivalent

performance under an intermittent schedule of drug reinforcement

but differ in the amount of responding emitted when the behavior

is extinguished. Such differences may relate to other behaviors

such as the probability of resuming drug self-administration when

the drug is again made available.

The complexity of drug-reinforced behavior has several implications for the analysis of genetic determinants. First, comparisons among strains should be made using several independent

variables and a range of values of each independent variable

e.g., a range of drug doses). Second, the complexity of the

behavior increases the number of possible mechanisms that may

account for strain differences. Third, the complexity of the

behavior makes the use of involved genetic methods such as selective breeding studies more difficult. Despite these problems,

genetic studies with animals are very important and should be

actively pursued, since they permit investigation of genetically

controlled mechanisms that may act in humans.

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ACKNOWLEDGMENTS

This work was supported in part by a grant from the University of

Minnesota's Office of Alcohol and Other Drug Abuse Programming, by

grant DA-00944 to R.A. Meisch from the National Institute on Drug

Abuse, and by New Investigator Research Awards AA-06104 and AA06924 to F.R. George from the National Institute on Alcohol Abuse

and Alcoholism.

AUTHORS

Richard A. Meisch, M.D., Ph.D.

Professor, Psychiatry and

Pharmacology

Department of Psychiatry

University Hospitals

University of Minnesota

Box 393, Mayo Memorial Building

Minneapolis, MN 55455

23
Frank R. George, Ph.D.

Behavioral Genetics Laboratory

Preclinical Pharmacology Branch

National Institute on Drug Abuse

Addiction Research Center

Baltimore, MD 21224

and

Department of Pharmacology

and Toxicology

School of Pharmacy

University of Maryland

Baltimore, MD 21201

24
Family Pedigree Studies of Biological

Vulnerability to Drug Dependence

James R. Stabenau

INTRODUCTION

Epidemiologic studies have characterized the frequency of behavioral disorders such as alcoholism and drug abuse/dependence in

the general population (Weissman et al. 1980; Robins et al. 1984).

Family pedigree studies have employed similar case finding methods

in surveys of biologically linked members in several generations

for probands with a given disorder (Winokur et al. 1970; Cotton

1979; Stabenau and Hesselbrock 1980; Rounsaville et al. 1982c;

Cloninger and Reich 1983; Mirin et al. 1984b). When rates of a

disorder in biological relatives of probands with the disorder are

significantly higher than in the general population, such data

provide the first order of confirmation for a genetic vulnerability hypothesis for the disorder (Cloninger and Reich 1983). When

rates for two disorders are compared in extended families of probands who differ for those two disorders, the dependence or independence of those two disorders may be statistically established

(Cloninger and Reich 1983; Hill et al. 1977; Merikangas et al.

1985a).

Thus, family pedigree studies represent the first stage in the

scientific assessment of genetic/biological vulnerability. Wellcontrolled pedigree studies provide sufficient information to

suggest that specific syndromes of clinical characteristics are

transmitted through families (Merikangas et al. 1985a; Cloninger

and Reich 1983; Winokur et al. 1970; Stabenau 1984). They also

provide the statistical basis for determining whether or not

different behavioral disorders are transmitted independently

(Cloninger et al. 1981a). For most behaviorally determined disorders, however, family pedigree studies are not as specific as

cross-fostering adoption studies in identifying discrete genetic

risk factors as separate from cultural rearing influences.

The major strengths of the family pedigree model are the capacities to explore hypotheses and the ease of accomplishment at low

cost compared to twin and adoption studies. In the study of substance abuse, where use of most drugs is illegal, case finding is

25
significantly easier among a series of related individuals than

among groups of adoptees or twins. The major limitation with the

family study method is that for any biological risk factor, the

genetic risk and family rearing experience are not readily separable as to independent effect. To achieve this, the adoption

cross-fostering model, where influences of biological and rearing

parents are separately controlled, is required (Goodwin et al.

1973; Cadoret and Gath 1978; Cloninger et al. 1981b). However,

when familial and cultural environmental factors are measured for

index probands plus their biological relatives and for control

probands plus their biological relatives, such variables can be

entered into statistical models along with estimates of genetic

risk (Rice et al. 1983).

The purpose of this paper is to review the results of application

of family pedigree methods in assessing biological vulnerability

for substance abuse including alcohol, heroin and other opiates,

cocaine and other stimulants, and hypnotic and sedative drugs.

This review includes the issues of clinical and genetic heterogeneity and potential personality and biochemical "correlates" of

substance-seeking behavior.

Research in substance abuse/dependence has been principally

directed at the phenomenology of drug abuse with predominantly

epidemiologic studies (Dembo et al. 1985). This approach, involving "what, where, and when research," has utilized theoretically framed models of social and environmental factors. Four

explanatory frameworks dominating the field are: (a) problem

behavior proneness (Jessor and Jessor 1977); (b) social learning

theory (Burgess and Akers 1966); (c) self-derogation theory

(Kaplan 1980); and (d) socialization theory (Kandel 1975). Of

these four, problem behavior proneness and the degree to which

individuals learn social norms might have a biological basis.

The concept of risk must not only assess the environmental and

cultural variables that place individuals at risk for drug use but

also the possible biological factors that may be under genetic

control. Such factors may constitute personality/behavior variables that could lead to drug-seeking behavior as a means of satisfying an inner neurophysiologic, neurochemical "need" (Inwang et

al. 1975). Recent efforts have been directed at identifying the

biological factors that may explain differences in drug-seeking

behavior, phases of initiation as well as cessation of chronic

use, and degrees of tolerance and dependence (Kauffman et al.

1984: Nahas 1981). Research must intearate the power of survey

methodology and statistical explanation with the understanding of

the subject's perception and definition of the initiation and

sustenance of drug use, if prevention is to become a possibility

(McBride and Clayton 1985). Study of brain mechanisms and drug

behavior is important, since psychoactive drugs act primarily on

the brain at both the molecular level, by altering neurotransmitter turnover among other things, and at the neuronal level, by

altering the function of key brain structures (Nahas 1981).

26
GENETIC HETEROGENEITY OF ALCOHOLISM

Genetic heterogeneity and risk hypotheses for alcohol abuse and

dependence have been tested (Cloninger and Reich 1983; Lewis et

al. 1983; Stabenau 1984; Stabenau and Hesselbrock 1984;

Hesselbrock et al. 1984; Cadoret et al. 1985; Stabenau 1986a).

Analysis of family pedigree data for DSM-III alcohol-dependent

subjects in a "typology" sample of 321 male and female inpatients

has demonstrated a high frequency (43 percent) of alcoholism

associated with DSM-III Anti-Social Personality diagnosis (ASP)

and a high frequency (89 percent) of subjects reporting a parent

or sibling of a parent who was alcoholic by Family History

Research Diagnostic Criteria (FHRDC) (Stabenau and Hesselbrock

1984). Using FHRDC methods for psychopathology diagnosis of

first-degree family members and spouses, evidence of considerable

assortative mating for alcoholism and ASP was also noted in this

sample (Stabenau and Hesselbrock 1980; Stabenau and Hesselbrock

1984).

A separate analysis of the first 210 volunteer DSM-III alcoholdependent patients (156 male and 54 female, with a mean age of 39

years) from the same "typology" sample has also been reported

(Stabenau 1984). The results suggested: (1) types of family history of alcoholism (FHA) were not related to the natural course of

alcohol dependence in male or female subjects; (2) ASP was significantly associated with an earlier onset of the first stages of

alcohol abuse; (3) compared with the probands having no family

alcoholism and those with alcoholism on one side of the family,

probands with alcoholism on both sides of their families experienced significantly more impaired control over their drinking

behavior, more physical symptoms, and more pathologic symptoms .

associated with chronic alcohol use; (4) women began the early

stages of alcohol abuse at a later age than men but reached the

later stages of alcoholism about the same time as men; (5) family

history, ASP, and gender did not differentiate this sample in

terms of age at first treatment for alcoholism; and (6) the sex of

the proband, the presence of ASP, and the type of family pedigree

for alcoholism were not interactive but contributed separate independent additive effects. Thus, this study suggested that factors under separate genetic control may be independently operative

in the pathogenesis of DSM-III alcohol dependence.

GENETIC HETEROGENEITY OF SUBSTANCE ABUSE/DEPENDENCE AND RISK

MODELS

A separate "high-risk" study consisted of 116 offspring with a

hospitalized DSM-III alcohol-dependent biological parent (i.e.,

parents were probands in the typology study) and 103 dental clinic

control subjects recruited for their participation in a "Health

Survey." This prospective study cohort (n=219) consists of 98

males with a mean age of 24.2 years and 121 females with a mean

age of 25.5 years. Methods similar to the typology study

(Hesselbrock et al. 1983) were employed, including the National

27
Institute of Mental Health Diagnostic Interview Schedule (NIMHDIS), estimates ofquantity and frequency of alcohol use, reasons

to drink or not to drink alcohol, the MMPI, and neurocognitive

testing (Stabenau 1986a). DSM-III criteria were applied to establish current and lifetime diagnosis of ASP and alcohol and/or drug

abuse/dependence. The distribution of lifetime alcohol or drug

abuse/dependence diagnoses was not significantly different for the

two subsamples. Fifty-five percent of alcohol abuse/dependence

subjects and 48 percent of drug abuse/dependence subjects were

offspring of alcoholics, while 45 percent of alcohol abuse/dependence subjects and 52 percent of drug abuse/dependence subjects

were dental control subjects (X2=1.4, df=2, and x2 = 5.1, df=2, NS.)

Family History Research Diagnostic Criteria (FHRDC) were used in

the diagnosis of parental alcohol abuse and/or dependence from

data provided by the proband. Fourteen male and six female proband subjects had lifetime DSM-III ASP diagnoses. For 40 percent

of the subjects, neither parent had FHRDC diagnosis of alcoholism,

while 31 percent had an alcoholic father, 15 percent had an alcoholic mother, and for 14 percent both father and mother were

alcoholics. Table 1 shows the lifetime rates of DSM-III alcohol

or drug abuse/dependence analyzed by genetic group (i.e., with (+)

or without (-) ASP diagnosis or family history of alcoholism

(FHA)). Alcohol and drug dependence rates were highest for ASP

subjects with or without a family history of alcoholism. Prevalence rates of dependence or abuse for either alcoholism or drugs

were consistently higher for males than for females. The lifetime

and current rates for alcohol abuse/dependence were 37.4 percent

and 18.2 percent for males and 19.1 percent and 9.2 percent for

females. Similarly, for drug abuse/dependence lifetime and current rates were 23.2 percent and 7.1 percent for males and 15.8

percent and 4.2 percent for females. ASP and FHA, when combined,

TABLE 1. Lifetime prevalence of DSM-III alcohol and drug abuse or

dependence by genetic group

ASP+ ASP+ ASP- ASPFH+ FH- FH+ FH- Total

n % n % n % n % n %

Alcohol Abuse 5 83.3 9 64.3 34 21.2 12 16.2 60 27.4

or Dependence*

X

2

=25.1, df=6, p<.001

Drug Abuse 4 66.7 7 50.0 20 16.0 11 14.9 42 19.2

or Dependence*

X

2

=13.9, df=6, p<.05

Total Subjects 6

in Group

14 125 74 219

*Some subjects have both diagnoses.

28
provided the greatest risk for lifetime alcohol and/or drug abuse/

dependence, with 66 percent of ASP+/FH+ and 35 percent of ASP+/FHsubjects receiving DSM-III diagnoses of alcohol and drug abuse/

dependence. The frequency of subjects with no alcohol or drug

dependence or abuse diagnosis was highest for those classified as

ASP- with either FH+ (63 percent) or FH- (82 percent).

Initial data have suggested that more individuals either remain

abusers of, or dependent on, alcohol and/or drugs or stop abusing

both. When they remit, they remit from both substances significantly more often than do other subgroups of subjects. Nine of

the twenty-nine subjects (31 percent) who currently abused or were

dependent on alcohol were also currently abusing or dependent on

drugs, while 11 of 31 subjects (35 percent) who remitted from

alcohol abuse or dependence had also remitted from previous drug

abuse or dependence (x2=62.4, df=4, p<.001) (Stabenau 1986a).

When ASP diagnosis, parental alcoholism, and gender were used as

risk terms, eight "phenotypes" were formed to describe liability.

A logistic regression model utilizing the three factors plus age

of the subject demonstrated that the improvement x2 was greatest

for ASP, then gender, and lastly for FH in describing the risk for

the development of a lifetime diagnosis of phenotypic alcohol

dependence and abuse. Age did not contribute to the description

of risk (Stabenau 1986a). The observed rates of liability for

lifetime diagnosis of DSM-III alcohol abuse and dependence in this

sample replicated the risk observed by Lewis and colleagues (1983)

for male and female medical and surgical patients (mean age 39

years) for a lifetime diagnosis of definite alcoholism established

with Feighner criteria. Table 2 shows the mean observed rate of

lifetime diagnosis of alcoholism from the two studies.

MODELS OF RISK FOR SUBSTANCE ABUSE AND DEPENDENCE

A genetic vulnerability hypothesis for alcoholism or alcohol

dependence has been supported by family pedigree (Winokur et al.

1970; Cotton 1979; Stabenau and Hesselbrock 1980), twin (Kaij

1960; Hrubec and Omenn 1981). and adoption studies (Goodwin et al.

1973; Cadoret and Gath 1978; Cloninger et al. 1981b). Alcohol dependence is heterogenous and appears to have three different subforms: primary alcoholism without family history of alcoholism;

primary alcoholism with a family history of alcoholism; and secondary alcoholism associated with antisocial personality disorder.

The latter two subforms have strong genetic vulnerability components (Cloninger and Reich 1983; Lewis et al. 1983; Stabenau 1984;

Cadoret et al. 1985; Merikangas et al. 1985a; Stabenau 1986a).

Base rates of risk for lifetime alcoholism are higher for males as

compared to females when family history of alcoholism and ASP

diagnosis are not present. Rates for both males and females are

twice as high as base rates when family history of alcoholism is

positive and especially when definite diagnosis of ASP is present

(table 2). However, diagnosis of depression and family history of

ASP have not been found to be correlates of risk for alcoholism

(Lewis et al. 1983; Cadoret et al. 1980).

29
TABLE 2. Mean lifetime risk of phenotypic alcoholism observed in

two studies* based upon gender, family history of

alcoholism in a first-degree relative, and antisocial

personality diagnosis of the proband

"Alcoholism"

Phenotype

Gender FHA ASP

Number of Number

Subjects "Alcoholic"

Percent

"Alcoholic"

M + + 19 17 89.5

M - + 28 15 53.6

F + + 26 7 26.9

F - + 26 8 30.8

M + - 73 28 38.4

M - - 107 21 19.6

F + - 140 22 15.7

F - - 209 13 6.2

*Lewis et al. 1983; Feighner Diagnostic Criteria for ASP and definite alcoholism

diagnosis; 131 males, 281 females. Stabenau 1986a; DSH-III Diagnostic Criteria

for ASP and "alcoholism” as alcohol abuse or dependence diagnosis; 98 males, 121

females.

Genetic studies of substances other than alcohol have included

family pedigree studies of dependent subjects and their biological

relatives (Lewis et al. 1983; Stabenau and Hesselbrock 1984; Mirin

et al. 1984b; Rounsaville et al. 1982c; Lewis et al. 1985a; Hill

et al. 1977) (table 3), several twin studies of patterns of substance use (Pederson 1981; Cederlof et al. 1977; Kaprio et al.

1978), and adoption studies with a primary focus on alcohol dependence or sociopathy and a secondary description of use of drugs

(Goodwin et al. 1973; Crowe 1974). It is difficult to compare

studies where substance misuse is described by different diagnostic classifications. Three operational systems which utilize

substance dependence behaviors and psychosocial consequences of

dependence are the Feighner criteria (Feighner et al. 1972), the

Research Diagnostic Category (RDC) criteria (Spitzer et al. 1978),

and the DSM-III criteria (American Psychiatric Association 1980).

Opioid dependence has been reported as heterogenous, but all three

diagnostic groups included substantial numbers of subjects with

DSM-III ASP diagnoses (Rounsaville et al. 1982b). In a study comparing opiate abusers to abusers of sedative-hypnotics and stimulants, most opiate abusers had ASP diagnoses (Mirin et al. 1984b).

Other studies of substance-abusing/dependent subjects have demonstrated rates of ASP diagnosis substantially higher (Lewis et al.

1983; Stabenau and Hesselbrock 1984; Rounsaville et al. 1982a;

30
TABLE 3. Rates of psychopathology in probands using DSM-III, RDC, and Feighner criteria in samples at

differing risk for substance abuse/dependence
TABLE 3. (Continued)
TABLE 3. (Continued)

REFERENCES FOR TABLE 3

a

Community Survey; Robins et al. 1984;

DSM-III; M=7,816; F=5,727.

b

Community Survey; Weissman et al.

1980; RDC; M=219; F=291.

c

Birth Cohort; Lewis et al. 1985b;

Feighner; M=223.

d

Medical and Surgical Inpatients; Lewis

et al. 1983; Feighner; M=131; F=281.

e

Alcohol Dependence; Stabenau and

Hesselbrock 1984; DSM-III; M&F=227;

M10=555; F10=555.

f

Alcohol Dependence; Cadoret et al.

1984; DSM-III M&F=179.

g

Substance Abuse; Mirin et al. 1984b;

DSM-III; M&F-160; M10=338; F10298,

h

Opiate Addiction; Rounsavllle et al.

1982c; RDC; M=403; F=130.

i

Narcotic Dependence; Croughan et al.

1982; Feighner; M=91; F=88.

j

Affective Disorder Study; Lewis et al.

1985a; RDC; M=216.

Rounsaville et al. 1982b; Rounsaville et al. 1982c; Croughan et

al. 1982; Cadoret et al. 1984; Lewis 1984) than in community survey populations (Robins et al. 1984). In those populations with a

substantially elevated frequency of ASP, rates of alcohol and

other drug abuse were both higher (Lewis et al. 1985a; Lewis et

al. 1985b) than several community survev rates (Robins et al.

1984). High frequency of affective disorder is seen in most

substance-abusing/dependent populations (Mirin et al. 1984a:

Rounsaville et al. 1982b; Rounsaville et al. 1982c; Croughan et

al. 1982; Lewis et al. 1985b) but is predominantly secondary to

drug dependence (Mirin et al. 1984a; Croughan et al. 1982).

However, stimulant abusers had significantly more first-degree

biological relatives with affective disorder than did opiate or

sedative-hypnotic abusers (Mirin et al. 1984b). One study demonstrated independence in the familial transmission of alcoholism

and opiate abuse, but biological relatives were not interviewed

for diagnosis (Hill et al. 1977). Comparative pedigree studies

should provide structured interviews (Robins et al. 1981) with all

available relatives utilizing dependence criteria (American

Psychiatric Association 1985).

PREFERENCE FOR ALCOHOL AND ALCOHOL-SEEKING BEHAVIOR AS A MODEL FOR

DRUG-SEEKING BEHAVIOR

To become dependent upon alcohol, there must be a choice to drink

alcohol, rather than not to drink alcohol. The multivariate approach to alcohol dependence has suggested at least four reinforcement contingencies for alcohol use or avoidance of alcohol

use and subsequent dependence (Caddy 1977). Positive biological

reinforcers for alcohol use include such items as "enjoyed the

taste" or "to help me sleep," and positive psychosocial reinforcers for alcohol use include items such as "just to be sociable" or

"to relieve boredom." Negative biological reinforcers and negative psychosocial reinforcers that might reduce alcohol use include items from “I don't like the effect it produces" to "my

33
parents disapprove." Subjects rated these items for themselves as

reasons for drinking or not drinking alcohol (Stabenau 1986b).

The reasons to drink or not to drink alcohol were compared for

subjects in the "high-risk" study (n=219). For the non-alcoholdependent/abusing subjects (n=159), there was a high positive

correlation between consumption of alcohol in the 6 months prior

to the study and reasons to drink and a negative correlation with

reasons not to drink. In this sample, males (37 percent) were

more frequently abusers of or dependent on alcohol and drugs than

were females (19 percent). A correlation between gender and reasons to drink or not drink alcohol demonstrated that there was a

significantly greater biological and psychosocial "preference" for

alcohol drinking among nondependent, nonabusing males as compared

to females.

Alcohol-seeking behavior was compared for DSM-III alcoholdependent individuals from the "typology" sample (Stabenau 1984).

Self-reported estimates of ounces of alcohol (as absolute)

consumed in the previous month, corrected for body weight at admission to the study, were compared. The conclusions were: Male

and female alcohol consumption corrected for body weight was not

related to age; male and female alcoholics showed no differences

when compared within subtypes of alcoholism; and, regardless of

sex, ASP alcoholics drank significantly more alcohol than non-ASP

alcoholics (Stabenau et al. 1986).

One method for evaluating drug-seeking behavior would be to evaluate personality variables that have been associated with risk for

substance abuse and concomitantly to evaluate potential biochemical correlates of neurotransmitter activity in a sample of hospitalized individuals and their biological first-degree relatives.

Personality variables may include high sensation-seeking behaviors

as measured by the Sensation Seeking Scale (Galizio et al. 1985);

elevations on the Psychopathic deviant (Pd), Mania (Ma), and

Depression (D) scales of the MMPI (Loper et al. 1973); and high

scores on impulsivity and monotony avoidance behaviors as measured

by the Karolinska Personality Scale (Rydelius 1983). There has

been little effort to test the relationship between such personality measures and clinical diagnosis of specific drug dependence

syndromes. Family pedigree studies would enable researchers to

compare family members based on differences in psychopathology

and/or personality phenotypes and different substance dependence

syndromes.

Potential markers of neurotransmitter activity include platelet

monoamine oxidase (MAO) activity and platelet serotonin (5-HT)

uptake. Low platelet MAO activity has been shown to be associated

with a number of disorders including depression (Murphy and Weiss

1972) and alcoholism (Wiberg et al. 1977). In addition, low MAO

was reported in the biological relatives of alcoholics (Sullivan

et al. 1979). Brain 5-HT has been shown to be lower in selectively bred strains of rats (Murphy et al. 1982), and 5-HT

uptake-inhibiting drugs can reduce alcohol seeking in such

34
alcohol-preferring strains (Amit et al. 1984). In humans, platelet 5-HT uptake has been reported as significantly lower for both

alcoholics (Kent et al. 1985) and depressed patients (Meltzer et

al. 1981). At present, it is difficult to determine whether low

5-HT uptake and low platelet MAO represent a primary "trait" or a

"state" secondary to the effects of alcohol use and/or depressed

affect. The study of such correlates should advance understanding

about whether MAO and/or 5-HT might serve as "markers" in prevention of alcohol- and/or drug-seeking behavior. Identification

of a significant relationship among first-degree relatives of

alcohol- and/or drug-dependent individuals for sensation-seeking

and monotony avoidance behaviors, platelet MAO and platelet 5-HT

uptake, and heightened alcohol- and/or drug-seeking behavior would

enhance screening for individuals at high risk for substance

misuse.

These data could have substantial impact for the prevention and

treatment of alcohol and/or drug dependence. For example, using

log linear regression models, any genetic or biochemical factors

found to correlate with lifetime risk for alcohol or drug dependence could be employed for establishing preventive programs in the

early school years. Also, by elaborating upon the predictors or

correlates for differential risk, more specific treatment programs

for dependence upon various psychoactive substances could be

developed.

CLINICAL AND GENETIC HETEROGENEITY OF SUBSTANCE ABUSE/DEPENDENCE

While a model of genetic heterogeneity for alcoholism has been

evolving, it is equally important to assess the degree of clinical

psychopathologic and genetic heterogeneity in individuals who are

drug abusers or drug dependent, in order to provide treatment that

is specific to any subform of drug dependence that may be etiologically related to different psychopathologic states and different

genetic vulnerability traits (Stabenau 1986c).

Table 3 lists the rates of psychopathology in probands in samples

at differing risk for substance abuse/dependence according to

DSM-III, RDC, or Feighner diagnostic criteria. When the studies

using similar diagnostic criteria were compared for psychopathology diagnosis (table 3), the following observations could be made:

The frequency of ASP among alcoholic and opiate addicts is higher

than for the general population, and the rates of alcoholism and

drug dependence are higher among ASP subjects as compared to nonASP subjects.

The rates of alcohol abuse, drug abuse, depression, and antisocial

personality among first-degree family members of probands with

such diagnoses frequently exceed those found in the general population. Independent genetic transmission has been proposed for

alcoholism (Cloninger and Reich 1983), ASP (Cloninger and Reich

1983), depression (Cloninger and Reich 1983; Merikangas et al.

1985b), and opiate dependence (Hill et al. 1977). A higher rate

of stimulant substance abuse was found among subjects who were

35
depressed and had significantly greater family history of depression as compared to depressant and sedative abusers (Mirin et al.

1984b). Opiate-dependent subjects and alcohol-dependent subjects

each had respectively more first-degree biological relatives with

opiate abuse and alcohol abuse (Hill et al. 1977). While ASP and

depression each had been considered as risk correlates of substance abuse (Rounsaville et al. 1982b; Mirin et al. 1984b), the

contribution of genetic vulnerability through family history of

psychopathology has only infrequently been assessed through controlled study of psychopathology variables in probands and firstdegree family members when evaluating substance abuse.

CONCLUSIONS

Family pedigree study of classes of substance abuse provides a

valuable method for assessing biological vulnerability or risk

factors for substance abuse and/or dependence. If biological

markers are identified in family pedigree studies, subsequent twin

and adoption studies of putative biological correlates of abuse/

dependence could provide a basis for distinguishing the genetic

factors from the cultural factors in their expression.

Alcohol abuse/dependence etiologic models have demonstrated a

genetic heterogeneity to the lifetime vulnerability of alcohol

misuse. Several personality and biochemical variables have suggested ways of researching the biological mechanisms of heightened

alcohol-seeking behavior. These methods may have similar applicability in the attempt to understand the biology of drug-seeking

behavior.

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ACKNOWLEDGEMENTS

This research was supported in part by grant AAO3510-06 from NIAAA.

AUTHOR

James R. Stabenau, M.D.

Department of Psychiatry

University of Connecticut

School of Medicine

Farmington, CT 06032

40
The Twin Method in the Study of

Vulnerability to Drug Abuse

Roy W. Pickens and Dace S. Svikis

INTRODUCTION

The twin study is a powerful research methodology for estimating

the relative contributions of genetic and environmental factors in

the development of a disorder. Apart from alcohol use, cigarette

smoking, and coffee drinking, however, the twin method has rarely

been employed in the study of drug abuse. The purpose of this

paper will be to (1) describe the rationale and assumptions of the

method, (2) review results of previous studies in the area, (3)

discuss limitations (and underlying assumptions) of the approach,

and (4) present preliminary results from an ongoing twin/family

study of alcoholism and drug dependence.

RATIONALE OF METHOD

In separating the effects of genes and environment, the twin method

capitalizes on differences in number of genes shared by monozygotic

(identical), and dizygotic (fraternal) twins. Monozygotic (MZ)

twins develop from a single fertilized egg that separates early in

development to create two genetically identical organisms. Because

they are genetically identical, any difference in the expression of

a disorder by members of an MZ pair can only be attributable to

nongenetic (environmental) factors. In contrast, dizygotic (DZ)

twins develop from two separately fertilized ova and are genetically no more alike than ordinary siblings. Because they share, on

the average, only half of their genes, any difference in the expression of a disorder by DZ twins may be due to genetic and/or

environmental factors.

Intrapair twin similarity for discontinuous measures (such as being

categorized as alcoholic or drug dependent) is expressed quantitatively by concordance, which is the proportion of cases where both

members of a twin pair are affected by a disorder (Plomin et al.

1977). Concordance rates may range from 0 (where none of the cotwins are affected) to 1 (where all of the cotwins are affected).

In estimating genetic and environmental influences, concordance

rates of MZ and same-sex DZ twins are compared. If MZ twins show

41
higher concordance rates than DZ twins, genetic factors are implicated. However, if MZ and DZ twins show similar concordance rates,

the role of genetic factors appears minimal. In estimating genetic

influences, absolute concordance rates are less important than

relative MZ/DZ differences, since absolute concordance rates are

determined by a number of factors including criteria used in diagnosing a disorder.

For continuous measures (e.g., number of symptoms or magnitude of

effect), genetic influences are typically estimated by calculation

of heritability (h2). Heritability is a population statistic that

describes the proportion of the observed variance that is due to

genetic factors (Plomin et al. 1977). Heritability values may

range from 0 (no genetic component) to 1 (all of the variance is

attributable to genetic effects). An estimate of heritability can

also be calculated from concordance rates for discontinuous

measures.

PREVIOUS STUDIES

Twin Studies of Substance Use

In the area of psychoactive substance use, fewer than 20 twin

studies have been reported. The majority of these studies have

focused on the quantitative aspects of substance use (Clifford et

al. 1984; Kaprio et al. 1981), rather than the clinical syndrome of

substance dependence. Findings with substance use may not generalize to substance dependence, however, as factors that contribute

to initiation and pattern of substance use may be different from

those involved in development of substance dependence.

The majority of substance use studies have focused on the heritability of alcohol drinking (i.e., quantity and frequency of

consumption). Results of these studies have been inconsistent.

For example, in two studies conducted with large twin samples, a

Finnish group reported significant genetic influences in frequency

and amount of alcohol drinking (Partanen et al. 1966), while a

Norwegian group found no genetic influences in similar measures

(Jonsson and Nilsson 1968).

Apart from alcohol, twin studies of other drug use have focused

primarily on cigarette smoking and coffee drinking. In the larger

studies, significant genetic effects for smoking status (i.e., ever

smoked) and quantity of coffee drinking (number of cups per day)

have been found, with over one-half of the variance being attributed to genetic factors (Kaprio et al. 1981; Pedersen 1981).

Apart from cigarette smoking and coffee drinking, however, twin

studies of other drug use have been rare. Of the reported studies,

most concerned the use of prescription drugs such as tranquilizers

and sleeping pills. Again, the results from these studies have

been contradictory, with some studies reporting higher concordance

rates for drug use in MZ than DZ twins, and others finding no

significant differences (Pedersen 1981).

42
Substance Dependence

The above studies focused on continuous measures of quantity and

frequency of substance use. From a clinical perspective, however,

it is more important to focus on categories of substance use (that

is, whether the proband met clinical criteria for being diagnosed

as alcoholic or drug dependent). Quantity and frequency of substance use are clinically distinguishable from substance dependence; a high level of substance use is a necessary but not

sufficient condition for the development of dependence. Most

definitions of dependence, for example, require evidence of

tolerance, physiological dependence, and/or harmful consequences

(American Psychiatric Association 1980; Feighner et al. 1972).

To date, only three twin studies of substance dependence have been

reported, and all concerned alcoholism rather than other types of

drug dependence. The first study was conducted in Sweden by Kaij

(1960). The probands were all males ascertained from County

Temperance Board registrations. In Sweden, an individual can

receive a Temperance Board registration for a variety of alcoholrelated problems, ranging from a single conviction for drunkenness

to heavy continuous abuse with social maladjustment and medical

complications. Zygosity was determined by similarities in appearance and, in doubtful cases, by blood-group analyses (n=58 MZ and

n=138 DZ pairs). Kaij found significant MZ/DZ concordance rate

differences for all levels of alcoholism, from least to most

severe. However, the MZ/DZ differences were greatest for the most

severe type of alcoholism, with concordance rates of .71 in MZ and

.32 in DZ twins.

The second study, conducted in the United States by Hrubec and

Omenn (1981), ascertained alcoholic twins by examining Veterans'

Administration (VA) hospital records (n=15,924 pairs). The probands were all males who had served in the U.S. Armed Forces.

Information on alcohol drinking problems was obtained from military

service records, VA records, and from questionnaires. Zygosity was

determined primarily by response to questionnaire items concerning

the similarity of the twins as children. These investigators reported higher MZ than DZ concordance rates for VA hospitalizations

with index diagnoses of alcoholism, alcoholic psychosis, and liver

cirrhosis. For alcoholism, concordance rates of .26 and .12 were

obtained, respectively, for MZ and DZ twins.

The third study was conducted by Gurling and colleagues (1981) in

Great Britain. These investigators examined concordance for the

alcohol dependence syndrome (rather than alcoholism per se) in both

males (n=28 pairs) and females (n=28 pairs). The twins were ascertained through a psychiatric twin register, and presumably included

probands with high rates of psychiatric disorders. Information

about drinking problems was obtained from official records and

personal interviews. Zygosity was determined by a physical

resemblance questionnaire and blood-group analyses. In contrast to

the results of the first two studies, Gurling and colleagues found

no evidence for genetic factors in alcoholism for either male or

43
female twins. In fact, there was essentially no difference in concordance rates for the disorder, with rates of .33 versus .30 in MZ

and DZ males and .08 versus .13 in MZ and DZ females.

Thus, the results of previous twin studies of alcoholism have not

been consistent. Although two studies found higher concordance

rates in MZ than DZ twins, the third study reported no significant

MZ/DZ differences. Also, in the two studies supporting a genetic

influence, there were differences in the absolute concordance rates

obtained (i.e., .71 versus .26 for MZ twins and .32 versus .12 for

DZ twins). There are a number of possible causes of these discrepant findings, including differences in criteria used to diagnose alcoholism, sampling errors due to recruitment bias, and

incorrect estimates of concordance rates due to inadequate sample

size (Svikis and Pickens, this volume).

ASSUMPTIONS OF TWIN METHOD

Interpretation of twin studies is only as good as the validity of

the assumptions on which the method is based. The first assumption

is that twins are representative of the general population. If

twins are not representative of singletons, then the results of

twin studies may not be generalizable to the population at large.

Although a number of factors distinguish twins from singletons

(e.g., twins have higher infant mortality rates), several studies

have shown that twin data generalize quite well to the larger

population; therefore, this assumption appears valid (Fuller and

Thompson 1978).

A second assumption is that MZ and DZ twins share equally similar

rearing environments. This assumption states that environmental

variance is constant across MZ and DZ twins, with the rearing

environment of MZ twin pairs being no more similar than that of DZ

twin pairs. A number of studies, however, have questioned the

validity of this assumption. Monozygotic twins have been found to

share more similar intrauterine and extrauterine environments than

dizygotic twins (Vandenberg 1976). In an effort to test the validity of the assumption, investigators have examined the relationship

between degree of environmental similarity and degree of behavioral

similarity across twin pairs. For a number of behavioral traits,

no significant relationship between these two measures has been

found (Loehlin and Nichols 1976). This suggests that, although MZ

twins may share more similar rearing environments than DZ twins,

this increased environmental similarity does not significantly

contribute to concordance rate differences in MZ and DZ twins.

The third assumption is parental panmictic mating. When estimating

the heritability of a particular disorder, the twin method assumes

that the parents of MZ and DZ twins have mated randomly. In alcoholism research, however, studies of spouse choice suggest that

parents of alcoholic individuals mate assortatively (Hall et al.

1983). That is, similarities in members of a spouse pair are

greater than expected if mating were random. Assortative mating by

44
parents of twins differentially affects the additive genetic variance shared by MZ and DZ twins. While MZ twins are unaffected,

assortative mating results in an increase in shared genetic variance for DZ twins. That is, DZ twins will appear more similar than

would be expected if parental mating were random. Thus, additional

research is needed to test the validity of this assumption in twin

studies of alcohol and drug dependence.

PRESENT STUDY

With these methodological issues in mind, we will present some preliminary data from an ongoing twin/family study of substance abuse.

These findings should be viewed as preliminary, as they are subject

to change as the size of our twin sample increases. Unlike previous studies, the present subjects were twin pairs in which at least

one member of each pair had been admitted for treatment of alcoholism or drug abuse. To minimize recruitment bias, the twins were

ascertained by screening all admissions to 16 alcoholism and drug

abuse treatment programs throughout the state of Minnesota, including public and private detoxification, outpatient, and residential

treatment programs for both adolescents and adults.

Participation in the study was a two-phase process. In the first

phase, both twins completed a brief questionnaire. In the second

phase, both participated in a personal interview and provided a

blood sample for definitive zygosity determination. To insure an

adequate sample size, when completed the present study is expected

to include data from at least 100 pairs of MZ and 100 pairs of

same-sex DZ twins. Also, to minimize volunteer bias, efforts will

be made to collect data from at least 75 percent of the twins

ascertained during the study. To insure participation, subjects

are paid $25 for questionnaire completion and $75 for the personal

interview.

The questionnaire collects data on demographics, lifetime pattern

of alcohol and other drug use, lifetime psychopathology indicators

(including psychiatric symptomatology and sociopathic behavior),

twin zygosity indicators, and alcohol/other drug use history in

first-degree relatives. In the personal interview, formal psychiatric diagnoses, current and most extensive alcohol use, family

alcoholism and psychiatric disorders, medical history, and personality assessment from each twin are obtained. Assessment was also

made of how well the twins knew one another, and each twin was

asked to report on the alcohol and drug use of the cotwin. Finally, we obtained a blood sample for definitive zygosity determination (based on similarity of serum proteins and RBC antigens) and

permission to examine school records for academic performance and

behavioral problems. In addition, corroborative information about

each twin's alcohol/drug use and family history is being obtained

from a significant other (usually the spouse).

Zygosity was determined by comparing twin pairs on responses to

questionnaire items about early behavioral and physical similarity

(i.e., "As children, were you and your twin as alike as two peas in

45
a pod?" and "As children, did people, even relatives, have difficulty telling you apart?"). While this approach has been previously shown to be 90 to 96 percent accurate in distinguishing

"normal" MZ and DZ twins (Cederlof et al. 1961; Cohen et al. 1973),

its accuracy has never been tested with a sample of alcoholic

twins. Therefore, when blood-group data had been collected for 43

pairs of twins, we compared the blood-group results to the results

of questionnaire data for zygosity determination. The proband

questionnaire data were found to be 91 percent accurate in determining zygosity. That is, in 91 percent of cases, substanceabuse twins were correctly classified as MZ or DZ on the basis of

their answers to the questionnaire items.

To date, data have been collected from both members of 139 pairs of

twins in which at least one member of each pair (proband) met DSMIII criteria for Alcohol Abuse/Dependence. The twins were categorized as MZ or DZ on the basis of questionnaire and/or blood-group

data. Based on this classification, 64 pairs were identical, and

75 pairs were fraternal. The demographic characteristics of the

two groups are described in table 1. The data for the MZ and DZ

twins were similar. The mean age for both was in the middle to

late thirties, approximately two-thirds of each sample was male,

and the majority were Caucasian. There were no statistically

significant differences between MZ and DZ twins for age, sex, or

race.

TABLE 1. Demographic characteristics of the sample

MZ Twins DZ Twins

Number of Pairs 6 4 7 5

Mean Age (Years)

Percent Male

35.2 38.7

63% 71%

Race

Caucasian

American Indian

Black

92% 99%

5% 1%

3% 0%

To examine the role of genetic and environmental factors in the

etiology of alcoholism, proband-wise concordance rates for DSM-III

diagnoses of Alcohol Abuse and/or Dependence were calculated.

Twins received a diagnosis of Alcohol Abuse if they reported both a

pattern of pathological use (e.g., morning drinking) and problems

resulting from alcohol use (e.g., losing a job due to drinking).

Twins received a diagnosis of Alcohol Dependence if they reported

either a pattern of pathological use or problems associated with

alcohol use and evidence of tolerance or withdrawal from alcohol.

46
Table 2 shows alcoholism concordance rates for MZ and DZ twins.

For lifetime prevalence of Alcohol Abuse/Dependence, the MZ concordance rate was .55, and the DZ concordance rate was .41. The

MZ/DZ difference was not statistically significant (.10<p<.20).

TABLE 2. Concordance for DSM-III Alcohol Abuse/Dependence

All Twins (n=139 pairs):

Monozygotic Twins (n=64 pairs)

Dizygotic Twins (n=75 pairs)

Males Only (n=93 pairs):

Monozygotic Twins (n=40 pairs)

Dizygotic Twins (n=53 pairs)

Females Only (n=46 pairs):

Monozygotic Twins (n=24 pairs)

Dizygotic Twins (n=22 pairs)

.55

.41

MZ/DZ Ratio=1.3

.70

.43

MZ/DZ Ratio=1.6*

.29

.36

MZ/DZ Ratio=0.8

*p<.02.

For males, the alcoholism concordance rates were .70 in MZ and .43

in DZ twins (table 2 The MZ/DZ difference was statistically significant at p<.02 (x2=6.5). In females, however, concordance rates

were .29 and .36, respectively, in MZ and DZ twins, a difference

that was not statistically significant. These results suggest that

genetic factors may be important in male but not female alcoholism.

The present findings for males agreed with the results of twin

studies by Kaij and by Hrubec and Omenn. All three studies found

significant MZ/DZ differences for male alcoholism. All three

studies disagreed with the results of Gurling et al., who failed to

find significant MZ/DZ differences for male alcoholism. The present findings agreed with those of Gurling et al., however, who

failed to find significant MZ/DZ differences in female alcoholism.

(Kaij's and Hrubec and Omenn's studies included only male alcoholics.) In adoption studies, Goodwin et al. (1974) have also

found evidence for genetic factors in male but not female

alcoholism.

In addition to alcoholism, we also examined concordance rates for

problematic use of other drugs (excluding alcohol and tobacco).

47
Problematic drug use was defined as psychoactive drug use resulting

in family, social, occupational, legal, health, or emotional problems for the twin. The sample consisted of 66 same-sex twin pairs

in which at least one member (proband) reported family, social,

medical, or occupational problems related to use of other drugs.

Of the 66 twins, 62 also met DSM-III criteria for Alcohol Abuse/

Dependence and were included in the previous analysis. Using the

same zygosity indicators described previously, we found 37 to be

monozygotic and 29 to be dizygotic twins. The mean ages of the MZ

and DZ twins were 31.2 and 32.4 years, respectively. The MZ sample

was 59 percent male, while the DZ sample was 55 percent male.

There were no statistically significant MZ/DZ differences for age

or sex. Because of the small number of subjects that would have

been involved in an analysis by type or class of drug, we did not

analyze the data separately, but for all drugs combined (table 3).

TABLE 3. Concordance rates for problematic drug use

All Twins (n=66 pairs):

Monozygotic Twins (n=37 pairs) .43

Dizygotic Twins (n=29 pairs) .28

Males Only (n=38 pairs):

Monozygotic Twins (n=22 pairs)

Dizygotic Twins (n=47 pairs)

Females Onlv (n=28 pairs):

Monozygotic Twins (n=15 pairs)

Dizygotic Twins (n=13 pairs)

MZ/DZ Ratio=1.5

.55

.31

MZ/DZ Ratio=1.8

.27

.23

MZ/DZ Ratio=1.2

Concordance rates for problematic drug use were .43 in MZ and .28

in DZ twins, yielding an MZ/DZ ratio of 1.5. The MZ/DZ difference

was not statistically significant (.10<p<.20). When examined by

sex of subject, concordance rates were .55 in MZ and .31 in DZ

males (MZ/DZ ratio=1.8), and .27 in MZ and .23 in DZ females

(MZ/DZ ratio=1.2). Neither difference was statistically significant (for males, .10<p<.20; for females, p>.80). Thus, while

similar MZ/DZ ratios were obtained for both alcoholism and

problematic drug use, because of the larger number of subjects

involved, only the differences for alcoholism in males were

statistically significant.

48
CONCLUSIONS

Twin studies offer a powerful research methodology for estimating

the relative contributions of genetic and environmental factors in

the development of a trait or disorder. In the area of substance

abuse, several twin studies of alcoholism have been reported, but

the method has rarely been used to study other types of drug

dependence. Such studies are needed, as their results would be

important in improving our understanding of the basic nature of

such disorders. However, twin studies are expensive to conduct,

and twin subjects who are drug dependent are difficult to locate.

In addition, research is needed to determine the validity of the

assumptions that underlie use of the twin method in studies of

alcohol and drug dependence.

If the results of such studies suggest a genetic component to drug

dependence, then it would be important to know whether the influence is drug specific (i.e., limited to a single drug), applies to

classes of drugs (e.g., sedatives, stimulants), or applies to

psychoactive drugs in general. Specific attention should focus on

the relationship between genetic factors in alcoholism and other

forms of drug dependence.

Use of twin data may also help to identify environmental factors

important in drug dependence. Because any differences between

members of an MZ pair must be due to environmental factors, a

comparison of MZ twins who are discordant for drug dependence may

suggest environmental factors that either predispose to or protect

individuals from developing the disorder. Such findings may be of

considerable clinical significance when applied in programs for

preventing drug dependence.

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similarity of diagnosis with the aid of mailed questionnaires.

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Clifford, C.A.; Hopper, J.L.; Fulker, D.W.; and Murray, R.M. A

genetic and environmental analysis of a twin family study of

alcohol use, anxiety, and depression. Genet Epidemiol 1:63-79,

1984.

Cohen, D.J.; Dibble, E.; Grawe, J.M.; and Pollin, W. Separating

identical from fraternal twins. Arch Gen Psychiatry 29:465-469,

1973.

Feighner, J.P.; Robins, E.; Guze, S.B.; Woodruff, R.; Winokur, G.;

and Munoz, R. Diagnostic criteria for use in psychiatry research Arch Gen Psychiatry 26:57-63, 1972

Fuller, J.L., and Thompson, W.R. Foundations of Behavior Genetics.

St. Louis: C.V. Mosby, 1978.

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Goodwin, D.W.; Schulsinger, F.; Hermansen, L.; Guze, S.B.; and

Winokur, G. Alcohol problems in adoptees raised apart from

alcoholic biological parents. Arch Gen Psvchiatry 28:238-243,

1974.

Gurling, H.M.D.; Murray, R.M.; and Clifford, C.A. Investigations

into the genetics of alcohol dependence and into its effects on

brain function. In: Gedda, L.; Parisi, P.; and Nance, W.E.,

eds. Twin Research 3: Epidemiological and Clinical Studies.

 New York: Alan R. Liss, Inc., 1981. pp. 77-87.

Hall, R.L.; Hesselbrock, V.M.; and Stabenau, J.R. Familial distribution of alcohol use: II. Assortative mating of alcoholic

probands. Behav Genet 13:373-382, 1983.

Hrubec, Z., and Omenn, G.S. Evidence of genetic predisposition to

alcoholic cirrhosis and psychosis: Twin concordances for alcoholism and its biological end points by zygosity among male

veterans. Alcoholism: Clin Exp Res 5:207-215, 1981.

Jonsson, E., and Nilsson, T. Alcoholkonsumtion,hos monozygota och

dizygota tvillinpar. Nordsk Hygienisk Tidskrift 49:21-25, 1968.

Kaij, L. Alcoholism in Twins. Stockholm: Almqvist and Wiksell,

1960.

Kaprio, J.; Koskenvuo, M.; and Sarna, S. Cigarette smoking, use of

alcohol, and leisure-time physical activity among same-sexed

adult male twins. In: Gedda, L.; Parisi, P.; and Nance, W.E.,

eds. Twin Research 3: Epidemiological and Clinical Studies.

New York: Alan R. Liss, Inc., 1981. pp. 37-46.

Loehlin, J.C., and Nichols, R.C. Heredity, Environment and

Personality. Austin: University of Texas Press, 1976.

Partanen, J.; Brunn, K.; and Markkanen, T. Inheritance of Drinking

Behavior. Helsinki: The Finnish Foundation for Alcohol Studies,

1966.

Pedersen, N. Twin similarity for usage of common drugs. In:

Gedda, L.; Parisi, P.; and Nance, W.E., eds. Twin Research 3:

Epidemiological and Clinical Studies. New York: Alan R. Liss,

Inc., 1981. pp. 53-59.

Plomin, R.; DeFries, J.C.; and Loehlin, J.C. Genotype-environment

interaction and correlation in the analysis of human behavior.

Psychol Bull 84:309-322, 1977.

Vandenberg, S.G. Twin studies. In: Kaplan, A.R., ed. Human

Behavior Genetics. Springfield, IL: Thomas, 1976. pp. 90-150.

AUTHORS

Roy W. Pickens, Ph.D.

Director, Division of Clinical Research

National Institute on Drug Abuse

Parklawn Building, Room 10A5600 Fishers Lane

Rockville, MD 20857

50
Dace S. Svikis, B.A.

Clinical Services Manager, Alcoholism

Treatment Services D-5-C

Francis Scott Key Medical Center

4940 Eastern Avenue

Baltimore, MD 21224

51
Etiologic Factors in Substance Abuse:

An Adoption Study Perspective

C. Robert Cloninger

INTRODUCTION

In this article, I will first review studies of the classification

and inheritance of alcohol abuse. Then I will describe the adoption study method, review recent findings about the prediction of

susceptibility to alcoholism from childhood antecedents, and relate

these findings to studies of the prediction of substance abuse in

general. Next, the neurobiological basis of susceptibility to substance abuse will be considered in relation to three neural systems

that have been suggested to mediate susceptibility to personality

disorders (Cloninger 1987b), anxiety states (Cloninger 1986), and

alcoholism (Cloninger 1987a). These neural systems are involved in

modulation of the activation, maintenance, and inhibition of behavioral responses to novel, appetitive, and aversive stimuli, including stimulants, opiates, and antianxiety drugs. It is proposed

here that drug-seeking behavior is a special case of exploratory

appetitive behavior and involves different neurogenetic processes

than does susceptibility to behavioral tolerance and dependence.

It is supposed that drug seeking and susceptibility to tolerance

and dependence may be modulated by three putative neural systems

whose functions can be behaviorally measured by quantitative

ratings of personality and stimulus-response learning patterns.

TYPE 1 AND TYPE 2 ALCOHOLISM

Two types of alcoholism were first identified in a large-scale

adoption study initiated in Sweden by Michael Bohman and his

coworkers. The subjects included all 862 men and 913 women of

known paternity who were born to single women in Stockholm, Sweden,

from 1930 to 1949 and were adopted by nonrelatives at an early age.

Most of the subjects were separated from their biological relatives

in the first few months of life, and all had their final placement

in the adoptive homes before they were 3 years of age. Information

about alcohol abuse, psychopathology, and medical treatment was

available for the entire lifetimes of the adoptees and their parents from hospitals, clinics, and several registers that are

systematically maintained in Sweden. Identification of alcohol

52
abuse, using these sources, identifies about 70 percent of alcoholics; those so identified are representative of alcoholics in

general, with no appreciable bias for either type 1 or type 2

alcoholics (Öjesjo 1980).

The adoption study was initiated to evaluate the relationship

between the clinical features of alcohol abusers on the one hand,

and the pattern of interaction of genetic and environmental factors

on the other. Alcohol abuse in the adoptive parents was not associated with an increased risk of abuse in the children they reared,

so there was no evidence that alcoholism is familial because children imitate their rearing parents (Cloninger et al. 1981; Bohman

et al. 1981). In contrast, biological fathers with any registered

alcohol abuse had a twofold excess of sons with alcohol abuse (22.8

percent of 268) compared to the sons of parents with no alcohol

abuse (14.7 percent of 571). Likewise, biological mothers with any

registered alcohol abuse had a similar excess of sons with alcohol

abuse (28.1 percent of 32) compared to sons of parents with no

alcohol abuse. However, alcohol abuse was significantly increased

in the adopted-away daughters only if the biological mother was an

alcohol abuser (9.8 percent of 51). not if the biological father

was an alcohol abuser (3.5 percent of 285), compared to the

daughters of biological parents with no registered alcohol abuse

(2.8 percent of 577).

These sex differences suggested that some types of alcohol abuse

may be heritable in both men and women, whereas other forms are

heritable primarily in men. In addition, alcohol abuse in the

families of female alcoholics was found to have adult onset of mild

abuse without associated criminal behavior (Bohman et al. 1981).

In contrast, families with alcohol abuse in the biological father

but not the biological mother were found to have teenage onset of

both criminality and alcohol abuse more often than families with

alcohol abuse in the biological mother (Cloninger et al. 1981).

Accordingly, the families with early onset of recurrent alcohol

abuse and criminality in the biological fathers, but not mothers,

were designated as showing type 2 or "male-limited" alcoholism.

The families with alcohol abuse in the biological mother, or with

alcohol abuse and minimal criminality in the biological father,

were designated as representing type 1 alcoholism. The actual

classification was based on a discriminant analysis that took into

account all available information about alcohol abuse and criminality in the biological parents (Cloninger et al. 1981).

Given this subdivision of the biological parent backgrounds of the

adoptees, we evaluated the interaction between the biological predisposition and the postnatal environment. Both genetic predisposition and postnatal provocation were found to be necessary for

adopted-away sons to express susceptibility to loss of control

(type 1) alcoholism (table 1). If the biological parents were type

1 alcoholics and if the adoptee was likely to be exposed to a

pattern of heavy recreational drinking, as expected in the homes of

adoptive fathers with unskilled occupations, there was more than a

twofold increased risk of severe alcoholism. If either a genetic

53
predisposition or a provocative postnatal milieu was present (but

not both), then the risk of alcohol abuse was lower than in the

general population. Consequently type 1 alcoholism has been

described as "milieu limited."

TABLE 1. Cross-fostering analysis of severe type 1 alcohol abuse

in men in the StockhoIm adoption study

Is Genetic Is Environmental Male Adoptees Obsereved

Background Backgound

Type 1? Severe? Total No. % With Severe Abuse

No No 376 4.3

No Yes 72 4.2

Yes No 328 6.7

Yes Yes 86 11.6*

*Risk is significantly increased compared to all others (x2=5.6, p<.02).

In contrast, in adopted-away sons of fathers with spontaneous

alcohol seeking (type 2), there was an increased risk of alcoholism

regardless of environmental background (table 2). In these

families, the risk of alcohol abuse was increased ninefold in the

adopted-away sons of type 2 alcoholic fathers compared to the sons

of all other fathers.

TABLE 2. Cross-fostering analysis of type 2 alcohol abuse in men

in the Stockholm adoption study

Is Genetic Is Environmental Male Adoptees Observed

Background Backgound

Type 2? Type 2? Total No. % With Type 2 Abuse

No No 567 1.9

No Yes 196 4.1

Yes No 71 16.9*

Yes Yes 28 17.9*

*Risk is significantly increased in those with type 2 genetic background compared to

others (p<.01).

54
Other aspects of the inheritance of alcoholism in adoptees have

been reviewed in more detail elsewhere (Cloninger et al. 1985;

Cloninger 1987a). These two groups of alcoholics also differ in

neuropsychological, neurophysiological, and neurochemlcal responses

to alcohol, as reviewed elsewhere (Cloninger 1987a).

INHERITANCE OF CLINICAL SUBGROUPS OF ALCOHOLISM

Many studies of the inheritance of substance abuse have treated

alcoholism and drug abuse as if they were discrete disease entities. However, factor- and cluster-analytic studies indicate that

social problems, medical problems, family problems, and core symptoms of dependence or loss of control are only weakly correlated

with one another (Cloninger and Reich 1983). In the past, Jellinek

emphasized the clinical importance of distinguishing alcoholics who

had persistent alcohol-seeking behavior ("inability to abstain

entirely") from others who could abstain from alcohol for long

periods but were unable to terminate drinking binges once they had

started ("loss of control") (Jellinek 1960a; Jellinek 1960b).

Jellinek assumed that these clinical differences were caused by

different sociocultural backgrounds, but it has recently been shown

that genetic factors are important antecedents of such clinical

differences.

Two syndromes of alcohol abuse that aggregate in different families

have been distinguished in terms of alcohol-related symptoms and in

terms of antecedent personality traits (Cloninger 1987a). The

characteristics that distinguish these two types of alcoholism are

summarized in table 3. In a large family study of hospitalized

alcoholics, the number of type 1 and type 2 symptoms were negatively correlated (r=-.23, p<.01) in the male relatives of alcoholics.

Women were usually type 1 alcoholics: type 1 symptoms were five

times more common than type 2 symptoms in women. In contrast, men

were more heterogeneous: type 1 and type 2 symptoms were equally

common in men (Gilligan et al. 1987). Furthermore, type 1 symptoms

were frequent in the male relatives of alcoholic women, whereas

type 2 symptoms were frequent in the male relatives of alcoholic

men. This suggested that the familial aggregation of type 1 and

type 2 alcoholism reflects differences In variables, such as

personality traits, whose expression is influenced by the sex of

the individual, but are inherited in the same way regardless of the

sex of the parent or child.

Type 1 alcoholics have the triad of personality traits that are

characteristic of individuals with passive-dependent or "anxious"

personality: they are high in reward dependence (that is, eager to

help others, emotionally dependent, warmly sympathetic, sentimental, sensitive to social cues, and persistent); high In harm

avoidance (that is, cautious, apprehensive, pessimistic, inhibited,

shy, and easily susceptible to fatigue); and low in novelty seeking

(that is, rigid, reflective, loyal, orderly, and attentive to

details). In contrast, type 2 alcoholics have the triad of traits

that are characteristic of individuals with antisocial personality,

which is the reverse of the configuration seen in passive-dependent

55
personality: high in novelty seeking (that is, impulsive, exploratory, excitable, disorderly, and distractible); low in harm avoidance (that is, confident, relaxed, optimistic, uninhibited,

carefree, and energetic); and low in reward dependence (that is,

socially detached, emotionally cool, practical, tough-minded, and

independently self-willed) (Cloninger 1987a).

TABLE 3. Distinguishing characteristics of two types of alcoholism

Type of Alcoholism

Characteristic Features Type 1 Type 2

Alcohol-Related Problems

Usual age of onset (years)

Spontaneous alcohol seeking

(inability to abstain)

Fighting and arrests

when drinking

Psychological dependence

(loss of control)

Guilt and fear about

alcohol dependence

Personality Traits

Novelty seeking

Harm avoidance

Reward dependence

after 25 before 25

infrequent frequent

infrequent frequent

frequent infrequent

frequent infrequent

low high

high low

high low

Individual differences in each of these three personality dimensions (novelty seeking, harm avoidance, and reward dependence) are

largely independent of one another (Cloninger 1986; Cloninger

1987b). However, different combinations of these traits lead to

unique integrated patterns of response to novel, appetitive, and

aversive stimuli. The characteristic behaviors that arise from

these functional interactions are summarized in figures 1 to 3,

showing the three possible two-way combinations of three personality dimensions (Cloninger 1986; Cloninger 1987b). Thus, alcoholics have the full range of personality traits seen in the general

population, but differ quantitatively in the frequency and combinations of those traits. Alcoholics also have variable patterns of

56
FIGURE 1. Interaction of two personaity dimensions:

Novelty seeking and harm avoidance

predisposition to seek out alcohol and to become tolerant of and

dependent on it. Consequently, it has been proposed that the varying combinations of these personality traits reflect differences in

brain systems that determine individual tendencies to seek behavioral reinforcement from alcohol and other drugs, or to become

tolerant and dependent following exposure to various drugs

(Cloninger 1987a).

Individuals with type 1 alcoholism, which is associated with guilt,

fear, and loss of control of drinking, usually begin to have problems in late adulthood after an extended period of exposure to

heavy drinking that is personally or socially encouraged, such as

drinking to relieve tension during "happy hours" after work. In

contrast, individuals with type 2 abuse, which is associated with

impulsive-aggressive behavior and other forms of risk taking,

usually begin to seek out alcohol and other drugs during adolescence and early adulthood, regardless of external circumstances.

Consequently, the patterns of inheritance or gene-environment

interaction seen in these two types of alcoholism are strikingly

different (Cloninger et al. 1981; Cloninger et al. 1985).

57
FIGURE 2. Interaction of two personality dimensions:

Reward dependence and harm avoidance

CLINICAL AND NEUROGENETIC ANTECEDENTS OF SUSCEPTIBILITY

Several prospective longitudinal and familial high-risk studies

have been carried out to evaluate the possibility that childhood

and adolescent personality traits are predictive of susceptibility

to later alcoholism. Most studies have found that the premorbid

traits characteristic of antisocial personality, including being

impulsive, aggressive, overactive, distractible, impatient, and

excitable, are predictive of alcohol and drug abuse in young adults

(Aronson and Gilbert 1963; Robins 1966; Jones 1968; McCord 1972;

Loper et al. 1973; Kammeier et al. 1973; Hoffman et al. 1974;

MacAndrew 1979; MacAndrew 1981; Vaillant 1983; Knop et al. 1985;

Hagnell et al. 1986). Furthermore, several prospective longitudinal studies, retrospective or cross-sectional studies, and family

studies have found that antisocial or impulsive traits are characteristic of most early-onset alcoholics and/or polydrug abusers,

but of only a minority of alcoholics with later onset (Cloninger et

al., in press). Later onset of alcoholism or abuse of antianxiety

drugs is associated with passive-dependent or oral personality

traits, such as crying easily, feeling guilty or worried, and being

rigid, pessimistic, inactive, and passive. In an important largescale prospective study, both antisocial and passive-dependent

personality configurations were found to increase the risk of later

58
FIGURE 3. Interaction of two personality dimensions:

Novelty seeking and reward dependence

alcoholism in the Berkeley and Oakland longitudinal studies of

child development (Block 1971). Boys with passive-dependent traits

were called "anomic extroverts" because they tended to cry easily

and to worry excessively even though they were usually friendly and

warmly sociable; they had a tendency to drink and smoke heavily in

middle adulthood, but had few or no behavioral problems during

adolescence. Boys with antisocial traits were called "unsettled

undercontrollers" because they had been impulsive, aggressive, and

disorganized since childhood; they had a history of risk taking,

including substance abuse, since adolescence. More recently,

Cloninger et al. (in press) showed that childhood ratings of high

novelty seeking, low harm avoidance, and low reward dependence were

each strongly predictive of alcohol abuse in early adulthood.

Extreme deviations in the opposite direction (high harm avoidance,

high reward dependence, and low novelty seeking) were also associated with increased risk of alcohol abuse, but this passivedependent configuration had a less prominent effect before 28 years

of age (which was the time of last information) than had the antisocial personality configuration, as expected, since type 1 alcohol

abuse usually begins in later adulthood.

Among 75 studies that report on associations within individuals

among alcoholism, drug dependence, and antisocial personality, 76

to 80 percent found positive associations between each possible

pair of these diagnoses (Grande et al, 1984). Individuals with

early onset of antisocial behavior are particularly likely to abuse

59
both alcohol and other prescribed or illicit drugs (Lewis 1984).

Not all studies have found a strong association between antisocial

personality and substance abuse. However, the non-antisocial

substance abusers tend to be individuals with adult onset of

problems with anxiety or depression, which is self-medicated with

alcohol and other antianxiety drugs.

In the Stockholm adoption study, it has been possible to identify

individuals at high risk for alcoholism based on their personal

history of anxiety or criminality, as well as the history of

alcoholism and criminality in their biological parents. Cognitive

anxiety or frequent anticipatory worrying is associated with the

personality trait of high harm avoidance, particularly when reward

dependence is high and novelty seeking is low (Cloninger 1986);

this pattern is similar to that associated with loss of control or

type 1 alcoholism. In contrast, individuals with high somatic

anxiety have the personality traits of high novelty seeking and low

harm avoidance, which are associated with spontaneous alcoholseeking behavior or type 2 alcoholism. The relationship between

personality and alcoholism was supported by the finding of

increased risk of alcoholism in individuals with either somatic

anxiety or cognitive anxiety (Cloninger et al. 1986). However, the

importance of distinguishing the two subtypes of substance abusers

was shown by the inverse relationship between cognitive anxiety and

criminality: adoptees with cognitive anxiety had fewer criminal

biological parents than in the general population, whereas adoptees

with somatic anxiety had more criminal biological parents than in

the general population (Cloninger et al. 1986).

This evidence of clinical and genetic heterogeneity among alcohol

abusers suggests that such heterogeneity may be even more obvious

in relation to drug abuse in general. Individuals with passivedependent or anxious personality traits (high reward dependence,

high harm avoidance, and low novelty seeking) seldom take risks or

seek out alcohol or other drugs at an early age. Furthermore, they

prefer antianxiety drugs and are often overstimulated by even mild

stimulants like caffeine. These individuals are susceptible to

cognitive anxiety and find antianxiety drugs strongly positively

reinforcing because of the reduction of anxiety. In contrast,

individuals with antisocial personality traits (high novelty

seeking, low harm avoidance, and low reward dependence) engage at

an early age in much exploratory appetitive behavior and impulsive

risk taking, including abuse of a wide variety of drugs, including

alcohol, stimulants, and opiates.

A NEUROBIOLOGICAL LEARNING MODEL OF SUBSTANCE ABUSE

The clinical and genetic heterogeneity observed among substance

abusers suggests the importance of personality variables in

understanding substance abuse. Elsewhere I have described in

detail the initial development of a tridimensional model of

personality and its relationship to three neural systems involved

in the regulation of behavioral inhibition, behavioral activation,

and behavioral maintenance (Cloninger 1986; Cloninger 1987a;

60
Cloninger 1987b). The stimulus-response characteristics of these

putative brain systems are summarized in table 4. Each system is

complex, involving multiple brain structures and neurotransmitters,

but each of the three brain monoamines (serotonin, dopamine,

norepinephrine) appears to have a major neuromodulatory role in

only one system. Neuropsychopharmacological information relevant

to drug abuse is summarized here for each of the three proposed

systems.

Behavioral Activation System

Novelty seeking refers to a heritable tendency toward frequent

exploratory activity and intense exhilaration in response to novel

or appetitive stimuli. It is hypothesized to reflect variation in

the brain's "incentive," or behavioral activation, system. Dopaminergic cell bodies in the midbrain receive inputs from several

sources and then project impulses to the forebrain, thereby possibly acting as a final common pathway for behavioral activation in

response to novel or appetitive stimuli (Routtenberg 1978; Wise

1980; Wise 1984; Wise and Bozarth 1982; Stellar and Stellar 1985).

Spontaneous exploratory behavior by mammals in a novel environment

is dependent on integrity of mesolimbic dopaminergic projections,

particularly from the ventral tegmental area to the nucleus accumbens (Kelley and Stinus 1984; Iversen 1977). Low doses of ethanol

have an excitatory effect on ventral tegmental area neurons, suggesting that this action of ethanol may provide a pharmacological

"reward" that would facilitate alcohol-seeking behavior (Gessa et

al. 1985). Dopamine agonists, like amphetamines and cocaine, as

well as alcohol, opiates, and opioid neuropeptides, facilitate

dopaminergic transmission and behavioral activation, whereas dopamine blockers, like haloperidol, reduce exploratory behavior and

responsiveness to positive reinforcement (Kelley and Stinus 1984;

Iversen 1977; Pickens et al. 1978; Wise 1984). Self-stimulation

with electrodes at sites of dopaminergic neurons is rapid and

accompanied by marked locomotor activation and positive reinforcement of eliciting behavior in mammals and by reports of subjective

experience of pleasure and satisfaction in humans (Heath 1964;

Stellar and Stellar 1985). Cocaine administration directly into

the frontal cortex and the nucleus accumbens also has positive

reinforcement effects (Goeders and Smith 1983). Administration of

opiates and opioid neuropeptides intravenously or into the ventral

tegmental area leads to positive reinforcement of behavior; such

positive reinforcement by opiates is similar to that seen with

dopamine agonists like cocaine or amphetamine rewarding effects,

and can be blocked or reduced by dopamine antagonists such as

pimozide or cis-flupenthixol (Ettenberg et al. 1982; Bozarth and

Wise 1983; Stellar and Stellar 1985). Thus, drug-seeking behavior

for ethanol, cocaine, amphetamine, and opiates all depend on

integrity of mesolimbic dopaminergic projections to the forebrain,

suggesting that dopamine has an essential neuromodulatory role for

activation of behavior in response to novel or appetitive stimuli.

61
TABLE 4. Three major brain systems influencing stimulus-response characteristics

Brain System Principal

(Related Personality Monoamine Relevant Behavioral

Dimension) Neuromodulator Stimuli Response

Behavioral Activation

(Novelty Seeking)

Dopamine Novelty

Potential rewards or their

conditioned signals

Potential relief of

monotony or punishment

or their conditioned

signals

Behavioral Inhibition

(Harm Avoidance)

Serotonin Conditioned signals for

punishment, novelty,

or frustrative

nonreward

Behavioral Maintenance Norepinephrine Conditioned signals for

(Reward Dependence) reward or relief of

punishment

Exploratory pursuit

Appetitive approach

Passive avoidance

Extinction

Resistance to

extinction
Drug-seeking behavior for dopaminergic drugs may be considered a

special kind of exploratory appetitive behavior. Administration of

dopaminergic drugs when a mammal is in a particular side of a

chamber leads to preference for the place that has been rewarded

(Stellar and Stellar 1985). Alcohol-preferring rats, which have

low basal dopamine concentrations in the cortex and nucleus accumbens, show greater locomotor activation and greater increases in

dopamine turnover after low doses of alcohol than do alcoholnonpreferring rats (Murphy et al. 1983; Waller et al. 1986; Li

1987). Rodent strains that show high exploratory activity and low

fearfulness behavior, such as C57BL mice, show greater alcoholseeking behavior than other animals. Rodent strains that show

little spontaneous exploratory or alcohol-seeking behavior, such as

BALB/c and DBA/2 mice, have a biphasic response to alcohol with

greater suppression of dopamine release with lower doses of ethanol

and smaller increases at higher doses than C57BL/6 mice (Nichols

1972; Tabakoff and Ritzmann 1979; Kiianmaa and Tabakoff 1983).

Long-term ethanol intake produces behavioral tolerance to the highdose depressant effects of ethanol, but not to these low-dose

activating effects.

Schuckit and coworkers have used inhibition of prolactin release by

dopamine to study the effects of alcohol on dopamine release in

human subjects who are at high or low risk for alcoholism (Schuckit

et al. 1983). Prolactin increased by 30 minutes and returned to

baseline by 90 minutes for the controls, but continued to decline

until 150 minutes for the men with a family history of alcoholism.

This is consistent with the hypothesis that much drug-seeking

behavior is caused by dopaminergic behavioral activation. Low

basal firing rates of dopaminergic neurons are thought to be associated with greater postsynaptic sensitivity to dopamine when it is

released, lower turnover of dopamine as measured by cerebrospinal

fluid concentrations, and greater novelty seeking. More detailed

reviews of the behavioral activation system are presented elsewhere

(Cloninger 1986; Cloninger 1987a; Cloninger 1987b).

Behavioral Inhibition System

Harm avoidance is a heritable tendency to respond intensely to

aversive stimuli and their conditioned signals, thereby facilitating learning to inhibit behavior in order to avoid punishment,

frustrative omission of expected rewards, and uncertainty about the

safety of novel stimuli. Harm avoidance may reflect variation in

the brain's "punishment" or behavioral inhibition system, which

includes the septohippocampal system, serotonergic projections from

the raphe nuclei in the brain stem, and cholinergic projections to

the frontal neocortex from the basal nucleus of Meynert near the

amygdala and perhaps from the midbrain reticular formation near the

ventral tegmental area. Ascending serotonergic neurons from the

raphe nuclei project to the limbic system, including the septum and

hippocampus, as well as to the prefrontal cortex. The septohippocampal system is thought to function as a comparator, checking

predicted against actual events, and then interrupting behavior

when the unexpected is encountered (Warburton 1977; Gray 1982).

63
Ascending serotonergic projections from the dorsal raphe nuclei to

the substantia nigra inhibit nigro-striatal dopaminergic neurons

and are essential for conditioned inhibition of activity by signals

of punishment and frustrative nonreward (Thiebot et al. 1984). In

response to novel stimuli, ascending cholinergic projections excite

the frontal cortex and stimulate release of stress hormones, such

as cortisol (Warburton 1977). In turn, frontostriatal projections

reduce exploratory activity by inhibiting dopaminergic neurons in

the caudate nucleus (Iversen 1977).

Ethanol, barbiturates, benzodiazepines, and other antianxiety drugs

block the expression of behavioral inhibition acquired by operant

conditioning in which a particular behavioral response is learned

to predict punishment, omission of rewards, or dangerous novel

stimuli. The clinical antianxiety effects of these drugs in human

subjects are strongly correlated with their effects on passive

avoidance learning in rodents (Sepinwall and Cook 1980; Stein

1981). These antianxiety effects are thought to be a consequence

of inhibition by gamma-aminobutyric acid of serotonergic neurons

originating in the dorsal raphe nuclei (Stein 1981). In any case,

the reduction of anxiety is positively reinforcing. Presumably as

a result of positive reinforcement by antianxiety effects of such

sedative drugs, serotonergic projections have been strongly implicated in the development of behavioral tolerance to the sedative

effects of alcohol. In rodents, the development of tolerance is

accelerated (and, conversely, loss of tolerance is slowed) by

procedures that increase serotonergic activity or postsynaptic

sensitivity, whereas the development of tolerance is slowed (and

loss is accelerated) by procedures that reduce serotonin effects

(Khanna et al. 1980; Kalant 1985; Le et al. 1981; Melchior and

Tabakoff 1981; Melchior and Tabakoff 1984).

In human subjects, serotonergic activity, as measured by cerebrospinal fluid concentrations of serotonin metabolites, is strongly

correlated with harm avoidance (Cloninger 1986; Linnoila et al.

1983; Banki and Arato 1983; Asberg et al. 1984; Brown et al. 1982).

Increased serotonergic activity also inhibits dopaminergic activity, so that dopamine and serotonin turnover are strongly correlated

in human subjects and other mammals (Agren et al. 1986). Consequently, high harm avoidance is expected to inhibit appetitive

exploration for dopaminergic drugs, like cocaine, amphetamines,

opiates, and ethanol, and to accelerate the development of behavioral tolerance and psychological dependence on antianxiety drugs,

like barbiturates, benzodiazepines, and ethanol. This expectation

is consistent with findings in clinical and family studies that low

harm avoidance is associated with type 2 drug-seeking syndromes and

high harm avoidance is associated with type 1 loss-of-control

syndromes.

Behavioral Maintenance

Reward dependence is hypothesized to involve variation in behavioral maintenance or resistance to extinction of previously rewarded

behavior (Cloninger 1986; Cloninger 1987a). This resistance to

64
extinction is hypothesized to result from facilitation of pairedassociate learning by a brain system that is activated primarily at

the onset of reward or the offset of punishment, thereby facilitating the formation of conditioned signals of reward or relief from

punishment. Norepinephrine seems to satisfy the characteristics

required of the major neuromodulator for this system and may play a

critical role in the learning of new paired associations (Frith et

al. 1985). The major ascending noradrenergic pathways arise from

the locus coeruleus in the pons and project to the hypothalamus and

limbic structures, then branch throughout the entire cerebral

cortex. Norepinephrine seems to modulate the general level or

"tone" of neuronal activity by inhibiting spontaneous firing rates

of affected neurons and simultaneously increasing their response to

other afferents; in this way, the signal-to-noise ratio is increased, permitting important stimuli to stand out from irrelevant

stimuli.

In human subjects, short-term reduction of norepinephrine release

by acute infusion of the alpha-2 presynaptic agonist clonidine

selectively impairs paired-associate learning, particularly the

acquisition of novel associations (Frith et al. 1985). Similar

cognitive deficits arise from long-term destructive lesions of the

locus coeruleus, as in Korsakoff's amnestic syndrome in which

norepinephrine and arginine vasopressin levels in the cerebrospinal

fluid are decreased. Vasopressin is known to enhance memory when

injected immediately after learning trials, but this enhancement is

dependent on integrity of the noradrenergic projections in the

dorsal bundle (i.e., dorsal longitudinal fasciculus) (DeWeid and

Bohus 1979; Kovacs et al. 1979).

Similarly, vasopressin injections maintain tolerance to alcohol

beyond the time it is usually lost, but this maintenance effect is

dependent on the integrity of the dorsal noradrenergic bundle

(Hoffman et al. 1983). In addition, acquisition of behavioral

tolerance to the sedative effects of ethanol is not possible after

destruction of noradrenergic projections in mice, or after destruction of both serotonergic and noradrenergic projections in the rat

(Khanna et al. 1980; Kalant 1985; Melchior and Tabakoff 1981;

Melchior and Tabakoff 1984). Furthermore, in rhesus monkeys, individuals with low basal noradrenergic activity at rest show more

severe depressive-like responses to separation and have greater

increases in norepinephrine release after receiving low doses of

ethanol (Kraemer et al. 1984; Kraemer et al. 1985). Furthermore,

abstinent alcoholics with low basal levels of norepinephrine

metabolites in their cerebrospinal fluid have greater psychological

craving and dependence on alcohol than do other alcoholics (Borg et

al. 1983a; Borg et al. 1983b). These observations, together with

evidence that noradrenergic activity is conditionally inhibited at

the onset of punishment or offset of rewards and that low basal

firing rates are associated with greater postsynaptic sensitivity

to norepinephrine, support the hypothesis that individuals with low

basal firing rates of the locus coeruleus will have a greater

tendency to respond to signals of reward, such as social approval,

and to persist in reward-seeking behavior even when frustrated. In

65
contrast, individuals with higher basal noradrenergic activity

(hence lower postsynaptic sensitivity to norepinephrine) will tend

to be less sensitive to social cues and to be more practical,

quickly stopping activities when they are no longer tangibly gratifying (Cloninger 1986; Cloninger 1987a).

Altogether, these findings support the suggestion from clinical and

genetic studies that high reward dependence reflects individual

differences in a brain system modulated by norepinephrine.

Furthermore, the findings provide preliminary support for the

hypothesis that reward dependence reflects neuroadaptive processes

that are critical in the acquisition of behavioral tolerance to the

sedative effects of drugs and in susceptibility to loss of control

of antianxiety drugs.

OVERVIEW AND CONCLUSIONS

A major obstacle in studying the inheritance of drug abuse is that

exposure to drugs varies widely in terms of both the type and the

amount of drugs that are used by family members, especially between

generations. Studies of the inheritance of drug abuse would be

most informative if they could focus on susceptibility factors that

are (1) stably expressed regardless of exposure to drugs, (2) predictive of later drug abuse or complications from drug exposure,

and (3) at least moderately heritable. The availability of such

stable and heritable risk factors would permit studies of relevant

heritable traits across generations that differ in exposure to

different types of drugs.

Recent advances in research on the inheritance of susceptibility

factors to alcoholism provide a model that could be even more

powerful when applied to drugs in general than when limited to a

single drug, like alcohol. The three personality dimensions of

novelty seeking, harm avoidance, and reward dependence seem to reflect variations in underlying brain systems that modulate behavioral responses to novel, appetitive, and aversive stimuli in

general, including various classes of drugs. Specific combinations

of deviations in stimulus-response characteristics are associated

with different patterns of response to drugs, including differences

in preferences for stimulant or antianxiety drugs. Individuals who

are high in novelty seeking and low in harm avoidance, as in antisocial or histrionic personalities, prefer dopaminergic agonists,

like cocaine and amphetamines, and have early onset of type 2 drug

abuse syndromes with inability to abstain and frequent antisocial

behavior. In contrast, individuals with high harm avoidance and

high reward dependence, as in passive-dependent or passiveaggressive personalities, prefer antianxiety drugs because the

relief of anxiety leads to strong conditioned signals of reward

that are highly resistant to extinction. Individuals who are high

in both novelty seeking and reward dependence, as in histrionic and

passive-aggressive personalities, have a predisposition to both

spontaneous drug seeking and to development of behavioral tolerance

and psychological dependence on drugs. Most important, these

adaptive personality traits have consistently been found to be

66
moderately stable from childhood to adulthood (Sigvardsson 1987)

and to have heritabilities from 40 to 60 percent (Cloninger 1986;

Cloninger 1987a). Furthermore, ratings of childhood personality

traits are predictive of later drug use (Cloninger et al., in

press).

Taking these personality traits as indices of intervening susceptibility factors in drug abuse, the variable exposure to various

types of drugs in family members becomes an advantage, rather than

an obstacle. In other words, the variation in exposure to drugs

becomes an informative natural experiment in which individuals with

similar quantitative personality configurations develop different

clinical outcomes in response to different environmental stimuli

(that is, the provocative stimuli of exposure to drugs in different

types or amounts). Unfortunately, many past clinical family

studies have treated drug abuse as if it were a discrete phenotype

that was inherited. It is more plausible to assume that susceptibility to drug abuse is heritable, but that drug abuse itself is

not heritable. Furthermore, use of the model described here facilitates integration of experimental work on neuroadaptive mechanisms

in nonhuman animals with clinical studies of human subjects who

vary in susceptibility to drug abuse. This has the important benefit of facilitating investigations that can test hypotheses about

the pathophysiology of signs and symptoms of drug abuse. Neglect

of the clinical and etiological heterogeneity among drug abusers,

combined with variable exposure patterns, has led to limited progress in understanding drug abuse. The opportunity is now available

to characterize the inheritance of drug abuse in human subjects in

terms of underlying neuroadaptive mechanisms.

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ACKNOWLEDGMENTS

This work was supported in part by Research Scientist Award

MH-00048 and Clinical Research Center grant MH-31302 from the

National Institute of Mental Health; Alcohol Research Center grant

AA-003539 from the National Institute on Alcoholism and Alcohol

Abuse; and a grant from the MacArthur Foundation Network on Risk

and Protective Factors in Major Mental Disorders.

71
AUTHOR

C. Robert Cloninger, M.D.

Professor of Psychiatry and Genetics

Washington University Medical Center

216 South Kingshighway Boulevard

St. Louis, MO 63110

72
The High-Risk Paradigm in Alcohol

and Drug Abuse Research

Ralph E. Tarter

INTRODUCTION

The high-risk paradigm is based on the assumption that the likelihood of developing a medical illness, behavioral disorder, or

psychiatric disturbance is not equally distributed in the population. A negative outcome may be influenced by organismic predisposition, and as such, vulnerability can be viewed as lying

along a spectrum ranging from low to high. For example, the offspring of a schizophrenic mother has a probability of about 1 percent for developing this condition (Mednick and Schulsinger 1968).

If there is also a history of perinatal insult, however, the likelihood of the child becoming schizophrenic increases to about 10

percent (Mednick and Baert 1980). Thus, the probability of an

adverse outcome (risk) is related to the number and type of characteristics (vulnerability) present in the individual.

Vulnerability can also be viewed as localized in one or more

levels of biological organization. With respect to alcoholism,

certain individuals show a genetically determined vulnerability

(Goodwin 1983; Cloninger et al. 1981), which may be expressed

through various biological pathways and reflected in neurochemical

(Gottfries 1980), neurophysiologic (Begleiter et al. 1984; Pollack

et al. 1983), neurologic (Lee-Feldstein and Harburg 1982; Hegedus

et al. 1984), endocrine (Schuckit et al. 1983; Monnelly et al.

1983), and behavioral (Alterman and Tarter 1983; Tarter et al.

1985a) deviations. The delineation of the vulnerability need not,

however, be reduced to biological mechanisms. For example, it is

more parsimonious to describe the risk for hepatitis from the

standpoint of a homosexual lifestyle rather than from a perspective of the biological determinants of homosexuality. Nonetheless, recent genetic research into the etiology of psychiatric

disorders and, in particular, alcoholism has revealed substantial

evidence pointing to their heritable basis. It is, therefore,

heuristic at this time to consider the biological and perhaps

behavioral manifestations of gene expression underlying the vulnerability to alcoholism, insofar as it may serve as a model for

clarifying the etiology of drug abuse.

73
In clarifying the risk for developing a substance abuse disorder,

where social policy and law enforcement regulates availability,

cost, and distribution of the putative addictive agent, it is safe

to conclude that factors besides biology influence the likelihood

of an unfavorable outcome. To cite one extreme example, the rate

of alcoholism is close to nonexistent in fundamentalist Moslem

nations where presumably the genotype is, nonetheless, present in

a segment of the population. It would thus appear that to understand fully the risk parameters of alcohol and other drug abuse,

biological and psychosocial factors must both be considered as

determinants of outcome.

The present paper addresses the rationale underlying use of the

high-risk paradigm and examines some of the factors that contribute to the results obtained. Following this discussion, the

strengths and weaknesses of this paradigm are briefly presented.

No attempt will be made here to review the plethora of findings

from studies that have employed the high-risk paradigm for elucidating the antecedents to drug and alcohol abuse. A comprehensive

review of this subject can be found elsewhere (Tarter et al.

1985a). Rather, the purpose of this discussion is to highlight

the conceptual and methodological issues that are involved in

using the high-risk paradigm.

RATIONALE FOR EMPLOYING THE HIGH-RISK PARADIGM

The assumption underlying use of the high-risk paradigm is that

individuals deemed to be at elevated risk are discriminable from

those at low risk according to some characteristic. With respect

to alcoholism, risk classification has most frequently been made

according to the presence or absence of alcoholism in another family member,

ling).

usually a first-degree relative (i.e., parent or sibInasmuch as alcoholism tends to run in families, it is

expected that the particular feature under study, if indeed comprising the vulnerability, is more frequently or more strongly

present in individuals with a family history of alcoholism. This

paradigm is based on the empirical demonstration of both a familial aggregation and transgenerational high prevalence of alcoholism (Cotton 1979; Goodwin et al. 1973).

Another approach for classifying subjects according to high and

low risk for development of alcohol abuse is guided by theory.

Using hypotheses regarding predisposition to alcohol use and

abuse, such studies have defined risk on the basis of sensation

seeking (Zuckerman 1972), left-handedness (Lee-Feldstein et al.

1982), and type A personality (Folsom et al. 1985)--characteristics which have been empirically linked to the risk for augmented

alcohol and substance abuse. Investigations in which several such

risk factors were analyzed together have revealed that it is the

total number of factors (more than the specific characteristic of

the vulunerability) which best predicts outcome. For example, in a

high-risk study of substance abuse, Bry and colleagues (1982)

reported that the total number of vulnerability characteristics

74
was more important than the specific type of risk factors in predicting cigarette, alcohol, and cannabis use.

Other vulnerability characteristics for substance abuse have also

been identified, including poor school performance, perceived use

of drugs by adults, psychological disorders (e.g., depression and

conduct disturbance), low self-esteem, perception of parental drug

use, low religious involvement, conflict with parents, excitementseeking behavior, lack of a sense of purpose, a reduced sense of

social responsibility, and childhood hyperactivity. These latter

characteristics, comprising the dispositional characteristics of

the individual, have been implicated to comprise vulnerability to

alcoholism and, in some studies, drug abuse as well. However,

each variable by itself has not been found to be a powerful predictor of outcome. Rather, as noted above, it is the aggregation

of such factors which appears to best predict outcome.

In summary, the classification of subjects into high- and low-risk

groups can be conducted according to either empirical or theoretical criteria. To date, theory-driven research has not been systematically conducted. Tarter et al. (1985a), for instance,

suggest that a temperament perspective of alcoholism vulnerability

may have heuristic value in elucidating both the characteristics

and mechanisms underlying alcohol and/or drug abuse vulnerability. Such an approach affords the opportunity to conduct multidisciplinary research into the genetic predisposition, its

biological manifestations, and the psychosocial factors which

predispose to either a favorable or an unfavorable outcome. To

date, one study employing this comprehensive research strategy has

been reported. The results, however, underscore the value of such

an approach (Werner 1986).

Contexts of Expression of the Vulnerability

Differences between high- and low-risk subjects have been observed

both while they were sober and during an acute alcohol challenge.

For example, while Schuckit (1985a) found no differences between

high- and low-risk subjects at baseline, after a challenge dose of

0.75 ml/kg of alcohol, the high-risk subjects exhibited less body

sway. Although these results are intriguing, it needs to be

emphasized that the results obtained regarding static ataxia are

still preliminary and are not entirely consistent across investigations. Differences across studies with respect to the subject

sample and method of measurement of ataxia undoubtedly have contributed to this lack of consistency. Nevertheless, the point of

this discussion is that the vulnerability may be expressed under

different organismic conditions. Indeed, it may even be specific

to how the drug is metabolized (Schuckit and Rayses 1979). The

evidence in this regard, however, is far from conclusive.

Other investigations have revealed that alcohol attenuates the

experience of stress for high-risk individuals. Sher and Levenson

(1982) reported that high-risk young adult subjects, classified by

their high score on the Minnesota Multiphasic Personality

75
Inventory (MMPI) and MacAndrew Scale and a low score on the

Cooperative Preschool Inventory Socialization Scale, obtained a

stress-dampening effect from alcohol. That is, subjects who are

behaviorally raucous and disinhibited, socially behaving in a

nonnormative fashion, experience a reduction in experienced distress following alcohol consumption. This effect was not observed

in the low-risk subjects. Heavy drinkers, unlike moderate drinkers, have also been found to experience an analgesic effect from

alcohol (Cutter et al. 1976). Moreover, several studies indicated

that persons at elevated risk may experience either a more positively reinforcing or less punishing consequence following their

first and subsequent experience with drugs and alcohol (Haertzen

et al. 1983). Thus, the emerging evidence indicates that the

state of the organism as well as the reaction to the substance may

be critical for identifying the presence of a vulnerability characteristic. Further complicating the picture is the observation

that cognitive variables may differentially affect the reaction to

alcohol in vulnerable individuals (Newlin 1985).

Composition of the High-Risk Sample

Not all individuals deemed to be at high risk are likely to become

alcoholic. Moreover, there is evidence indicating that there may

be more than one type of genetic predisposition to alcoholism

(Cloninger et al. 1981). An important issue, therefore, concerns

the criteria for selection of individuals who comprise the highrisk sample. This is especially salient, since the age of onset,

familial characteristics, and premorbid characteristics may help

to distinguish among the various subtypes of individuals who

eventuate to an alcoholism outcome.

Another important consideration concerns whether or not current

drinkers and drug users should be included in the sample of highrisk individuals. Whereas this is not an issue for the study of

very young children, it is of consequence where the sample comprises adolescents or older subjects, since the effects of the

experience with alcohol or other substances may themselves be determinants of the characteristics that are otherwise presumed to

be associated with the vulnerability. In a recent study, it was

found that when current young adult heavy drinkers were excluded

from a high-risk sample, the score on a socialization scale no

longer discriminated high- from low-risk individuals (Sher 1985).

This finding suggests that the presence of certain vulnerability

characteristics may be detectable in only those persons at greatest risk; namely, individuals who have already commenced heavy

substance use. Thus, depending on the age of the sample, a tradeoff must be contemplated where the inclusion of current drinkers

could potentially confound the results obtained.

Specific vs. Generalized Vulnerability Characteristics

Studies of alcoholism vulnerability have not attempted to systematically ascertain whether the characteristics found in high-risk

76
subjects are also present in persons at risk for other psychopathological disorders including drug abuse. For example, low MAO

levels may not be a specific characteristic associated with risk

for alcoholism, since this finding has also been reported in other

psychopathological conditions such as depression and schizophrenia

(Bucksbaum et al. 1976).

Also, controlling for the presence of antisocial disorder reveals

no differences in childhood hyperactivity between high- and lowrisk subjects (Tarter et al. 1985b). Childhood hyperactivity has

been implicated in family, high-risk, and longitudinal research to

comprise one aspect of the vulnerability to alcoholism in men

(Tarter et al. 1985b); however, this behavioral disposition does

not appear to be specific to just an alcoholism outcome.

A particularly salient issue concerns whether the same vulnerability underlies alcohol and other drugs of abuse. Although there is

a paucity of research on this issue, the available findings do indicate that alcohol and substance abusers share a number of similarities (Lang 1983). It has even been argued that there are

commonalities among all disorders of excess, including gambling,

sexual conduct, and drug and alcohol abuse (Orford 1985). Peele

and Brodsky (1975) proposed that substance abuse is but one particular type of manifestation of an underlying vulnerability to

developing a compulsive disorder.

Further evidence pointing to a certain degree of commonality among

alcohol and drug abusers stems from the very high co-occurrent use

of such substances (Carmody et al. 1985; Newcomb et al. 1986). It

is also interesting to note that alcoholics prefer amphetamines as

the second drug of choice (Cadoret et al. 1984), suggesting that

the consumption of alcohol may not relate to only one specific

pharmacologic effect. It is possible, although as yet empirically

untested, that different drugs may be used by the same person

under various circumstances in the same way that a jukebox is

played to satisfy one of several different types of musical needs.

Moreover, it is a well-documented clinical phenomenon that the

cessation of use of one substance often results in the abuse of

another. In particular, alcohol and the benzodiazepines have been

linked in this regard (Vaillant 1983). Vaillant and Milofsky

(1982) also report that other pathways to recovery from alcoholism

are substituting smoking and candy for alcohol. These data indicate that there may be a common proclivity for substance abuse.

In summary, the available evidence indicates that alcohol and drug

abusers may share a number of common characteristics, perhaps

pointing to a common basis for the vulnerability. It is conceivable that there is a genetic predisposition to substance abuse,

but that the particular agent abused is determined by sociocultural and economic factors as well as the availability of the

substance. Also, it is quite possible that socialization factors

may lead vulnerable persons to develop other types of psychopathology as well. For example, individuals with anorexia nervosa

and borderline personality have higher rates of alcoholism in the

77
family. These individuals also show psychological characteristics

similar to those of alcohol abusers (Tarter et al. 1985a). Guze

(1975) has argued that hyperactivity in childhood places females

at risk for Briquet's Syndrome and males at risk for antisocial

personality disorder. Thus, there may be a common vulnerability,

or at least a number of shared characteristics, among a variety of

psychopathological disorders.

It should be pointed out, however, that appropriate studies have

not, as yet, been conducted either to confirm or refute this

supposition. Specifically, paradigms have not incorporated highrisk control groups that can allow for the differentiation of

vulnerability characteristics associated with different types of

substance abuse from those associated with other forms of

psychopathology.

Vulnerability and the Environment

As used in this discussion, vulnerability denotes a characteristic

that predisposes an individual to a negative outcome. Presumably,

the greater the vulnerability, the lower the required impact of

environmental factors to induce an unfavorable outcome. At present, however, the interaction between the type and magnitude of

organismic vulnerability and environmental stressors in the development of substance abuse has not been carefully researched.

Studies are needed to clarify the organismic and environmental

factors that could conjointly protect the person from an adverse

outcome. Field and population studies have implicated a number of

environmental variables which appear to influence both the onset

and maintenance of alcohol and drug abuse. For example, peer influence, socioeconomic status, cost and availability of the substance, and demographic status all contribute to the likelihood of

a child's developing a pattern of habitual drug or alcohol use.

Research is needed, however, to delineate how these latter factors

interact in the vulnerable person to ultimately influence the

outcome.

Summary

The above brief review illustrates that there may be numerous

vulnerability characteristics that exist across multiple levels of

biological organization which portend future alcohol or drug

abuse. These vulnerability features may be manifest either dispositionally (i.e., in the drug-free state) or specifically during

drug or alcoholic intoxication. From a methodological and sampling standpoint, the identification of vulnerable individuals can

be made according to empirical criteria, such as the frequently

documented association of substance abuse within families, or

according to some theoretical supposition regarding the physiological or psychological propensities for substance abuse. The

heterogeneity of the population of alcohol and drug abusers and

the fact that the vulnerability characteristics may be evident

only during specific stages of an individual's life illustrate

78
some of the difficulties involved in elucidating the predisposition to substance abuse. Furthermore, there is the important

theoretical issue concerning whether alcoholism vulnerability is

distinct from the predisposition to other types of drug abuse,

other forms of addictive behavior, and/or other forms of psychopathology. Finally, the micro- and macroenvironments, by providing the opportunity for an unfavorable outcome, emphasize the need

for learning more about how and by what pathways the vulnerability

ultimately leads to psychopathology in adulthood.

A DIATHESIS-STRESS MODEL OF ALCOHOL AND DRUG ABUSE ETIOLOGY

The above discussion illustrates that numerous variables comprising organismic vulnerability combine with a variety of environmental factors to impact on individuals in a complex fashion. A

simple cause-and-effect model of alcohol or substance abuse etiology is clearly inadequate, since either a positive or negative

outcome ultimately is determined by a wide range of factors and

their idiosyncratic interplay within the individual. Since it is

not unreasonable to conjecture that there are potentially many

different pathways to either a good adjustment or, alternatively,

an unfavorable outcome, an indeterminate model of substance abuse

etiology can be proposed. This model asserts that there is no

single necessary or sufficient causal variable underlying the

development of alcohol or substance abuse. Rather, the route to a

negative outcome varies within the population and is less than

certain for any given individual.

Figure 1 graphically illustrates how this model relates organismic

vulnerability to outcome risk. The figure depicts some of the key

environmental factors which can attenuate or exacerbate the vulnerability to produce a particular degree of risk for the individual. In this model, it is important to note that the vulnerable

person does not merely react passively to the environment but

plays an active role in shaping his or her environment. To cite

one example, it is noteworthy that a young child with a difficult

temperament (Thomas and Chess 1977) is more inclined to elicit

negative reactions from primary caregivers. In similar fashion,

parental reaction in turn influences the child's developing behavioral repertoire and emotional adjustment. Thus, the psychological characteristics comprising the vulnerability to substance

abuse should be viewed as the dispositions of an active organism

that reacts to, as well as creates, environments that can potentially increase or decrease the risk for an adverse outcome in

adulthood. Since temperament traits are largely influenced by

genetic factors and may comprise the behavioral correlates of

alcohol and drug abuse vulnerability (Tarter et al. 1985a). this

example is most salient to the present discussion. If temperament

contributes to vulnerability, then it would be important to examine how these traits are modified by environmental influences during infancy to produce specific personality styles that predispose

to substance abuse.

79
FIGURE 1. Diathesis-stress model

As shown in figure 1, the family is the first and probably the

most important influence on the psychosocial development of the

child. Numerous factors related to child-rearing style and family

organization have been implicated to importantly influence the

child's adjustment. These factors, operating on the vulnerable

child, can thus exacerbate the vulnerability so as to ultimately

augment the risk of an unfavorable outcome. For example, it is

not uncommon for children of alcoholic parents to be physically

abused. In one study (Tarter et al. 1984). it was shown that

physically abused children obtain lower scores on tests of intellectual capacity, educational achievement, and neuropsychological

capacity. It is thus not clear, however, whether the poor cognitive performance reported in children of alcoholics is due to an

inherited limitation or to their disrupted homelife and other environmental factors. Additionally, parental modelling of alcohol

excess and aggression, poor development of competency in school

(thereby increasing the likelihood of social deviancy), low intellectual capacity (resulting in poor and maladaptive problemsolving skills), and family disorganization (resulting in the

absence of an opportunity to develop appropriate social and personal values) contribute to the risk for an adverse outcome.

Apart from one genetic study (Cloninger et al. 1981) and one

short-term outcome study that has yet to follow the subjects into

the period of maximum risk (Werner 1986), no attempts have been

made to elucidate how family characteristics interact with the

vulnerable child to attenuate or exacerbate the risk of an unfavorable outcome. The study by Tarter et al. (1984), however,

illustrates that there are potentially numerous family influences

that could substantially influence outcome.

80
Apart from the immediate milieu of the family, the social reference group of the child, consisting of both informal friendship

patterns and formal institutional affiliations, also exercises a

major influence on the development of behavioral patterns, attitudes, and values. These institutional and peer influences are

embedded within the larger socioeconomic and cultural framework

that contains both the symbols and sanctions regarding the appropriate and inappropriate use of drugs and alcohol. Peer influence

in adolescence is an especially important factor in facilitating

deviant behavior, especially nonnormative use of drugs and alcohol. Peer influences can also have a protective effect through

strong negative sanction (e.g., church involvement) as well as

group identification (e.g., Al-Ateen).

The period from midadolescence to young adulthood is probably the

period of maximum risk for developing problems with the habitual

use of licit and illicit pharmacological substances. The controlling influence of the family is diminished substantially by midadolescence, and the child is under increasingly greater influence

by peers. Greater autonomy combined with some discretionary fiscal resources afford the opportunity to select the lifestyle and

environment that either facilitate or diminish the likelihood of

substance abuse. Depending on the work environment and social

affiliations, ambivalence and implied acceptance of substance use

can substantially augment the risk for an unfavorable outcome in

vulnerable individuals.

Finally, it should be noted that macroenvironment controls, which

regulate the sale and distribution of alcohol and drugs, can also

exert an effect on outcome. For example, while Prohibition was

not a popular policy for eliminating alcohol consumption, it did

reduce the incidence of liver cirrhosis. Thus, it appeared to attenuate some of the problems associated with chronic and excessive

use of alcohol.

In conclusion, biological or behavioral vulnerability alone does

not necessarily culminate in an unfavorable outcome. Rather,

numerous environmental variables interact with the vulnerable person to determine the magnitude of risk. However, it is reasonable

to conjecture that the greater the vulnerability, the less the

environmental stress required to produce an unfavorable outcome.

As yet, studies of high-risk samples, attempting to elucidate the

sequential events that occur during psychosocial development to

maximize the risk for alcoholism or drug abuse in adulthood, have

not been conducted. Moreover. studies are needed to clarify why

certain vulnerable individuals are able to avoid a negative out:

come in adulthood, which is of great importance from the standpoint of prevention intervention.

ADVANTAGES AND DISADVANTAGES OF THE HIGH-RISK PARADIGM

Results obtained using the high-risk paradigm do not predict or

provide an estimate of the risk for an adverse outcome. They

81
merely differentiate individuals, with varying degrees of specificity, according to some putative dimension. Risk, as noted previously in this discussion, must be viewed in the context of

numerous subject characteristics interacting with various environmental parameters and determined only upon longitudinal followup. Definitive conclusions about alcohol and drug abuse etiology

are not, therefore, obtainable by the use of the high-risk paradigm alone. The high-risk research strategy, however, has several

noteworthy advantages and disadvantages which were reviewed by

Schuckit (1985b).

The advantages include:

Subjects can be recruited from the nonclinical population;

thus, problem behaviors or other features of the vulnerability

can be studied in persons who have not been affected by treatment interventions.

Used in conjunction with a prospective longitudinal study, the

high-risk paradigm can potentially reveal the predictors of

outcome and determine how vulnerability and environmental variables interact to ultimately influence the outcome.

The high-risk paradigm enables unequivocal demonstration of

whether certain characteristics of alcoholism or drug abuse may

in fact presage the condition. (For example, low MAO levels,

antisocial tendencies, a field-dependent perceptual style, and

learning and memory problems are among the reported characteristics associated with alcoholism; however, whether these characteristics, implicated to comprise alcoholism vulnerability,

fully or partially antedate drinking onset, or are the consequence of alcohol abuse, remains unsettled.)

The disadvantages include:

 Without conjointly conducting a high-risk and longitudinal

study, it is not possible to ascertain whether any variable

discriminating high- from low-risk subjects is actually related

to outcome.

 The high-risk approach yields correlative, not causal, associations between vulnerability characteristics and outcome.

 It is difficult to document or control for serendipitous environmental events in tracking the pathway to a negative outcome.

 It is difficult to control for the effects of psychiatric illness in second-degree relatives, the effects of assortative

mating, verifying the pedigree, and a host of other relevant

factors that could substantially influence the results

obtained.

82
SOCIAL AND CLINICAL APPLICATIONS OF THE HIGH-RISK PARADIGM

Prevention interventions can be targeted specifically to the population at known heightened risk rather than to the whole population. Prevention, which currently consists of general didactic

interventions, could be directed specifically at identified features of the vulnerability. Once the vulnerability characteristics are revealed, the effectiveness of treatment interventions

for already affected persons may be markedly improved. For instance, high activity level during childhood may predispose to

alcoholism. Studies suggest that stimulant medication may be

therapeutic for both high activity level and some forms of alcoholism (Wood et al. 1976).

SUGGESTED DIRECTIONS FOR FUTURE RESEARCH

A major, if not central, issue concerns delineating both the general as well as the specific aspects of childhood vulnerability

that predispose to an adverse outcome. In carrying out such

research, a multidisciplinary theory-driven strategy is essential

that not only distinguishes children at high risk for alcohol and

substance abuse from normals, but also from groups of other children at risk for other psychopathological disorders. In this regard, research should be broadly based to include subjects at high

risk, but who eventually make a successful adjustment. Thus, by

combining the risk paradigm with prospective longitudinal research, the pathways to both positive and negative outcomes can be

determined.

Attention should be given to special groups. For example, neonates afford the opportunity to learn about genetic factors that

are relatively unaffected by environmental influences. Low-risk

groups can yield valuable information about the factors which

could protect the person from an adverse outcome. To this end,

cross-cultural studies should be very informative in clarifying

both the dimensions of vulnerability and the dynamic interplay of

factors which determine ultimate risk status.

Finally, a reevaluation of alcohol and drug abuse research at the

national policy level is recommended. To determine whether there

are distinct features that differentiate children at risk for

alcoholism from those at risk for substance abuse as well as from

children at risk for other psychopathology requires a stable

source of multi-institute funding. Perhaps a national center

could be targeted for such research that derives support from the

various agencies having a stake in these problems--specifically,

the institutes within the Alcohol, Drug Abuse, and Mental Health

Administration (ADAMHA) and the National Institute of Child Health

and Human Development. In this fashion, comprehensive and coordinated research into the early identification and prediction of

outcome in children at high risk for alcohol and substance abuse

can be conducted most efficiently.

83
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AUTHOR

Ralph E. Tarter, Ph.D.

Department of Psychiatry

University of Pittsburgh Medical School

3811 O'Hara Street

Pittsburgh, PA 15213-2593

86
Personality Factors in Drug Addiction

James N. Butcher

INTRODUCTION

The question as to whether there is an addictive personality has

been addressed many times in the past. Ancient writings give

clear awareness of the idea of an alcoholic personality, with the

implication that the condition was hereditary. For example,

Plutarch (Langhorne and Langhorne 1853) observed that "Drunkards

beget drunkards." Writings during the 19th century commonly

emphasized the hereditary nature of alcoholism and the importance

of personality factors and personal deterioration in drunkenness

(Gustafson and Gustafson 1888).

In spite of the fact that elements of character have long been

considered instrumental in the development of addictive problems,

evidence for an "addictive personalty" pattern has heretofore

eluded researchers. The idea that a unitary set of personality

factors precedes and results in the development of addictive disorders has not been widely accepted in alcohol and drug treatment

research and theory (Syme 1957; Sutherland et al. 1950; Jellinek

1960). The failure to isolate a personality pattern that is consistently associated with eventual development of drug or alcohol

problems has caused some researchers to minimize any causal role

for personality factors in substance abuse.

The fact that a causal link between a unitary "addictive personality" and the development of drug and alcohol problems has not been

consistently identified, however, does not eliminate personality

factors from the causal chain. There is a great deal of evidence

to indicate that personality factors play an important part in

understanding patterns of addiction. A number of recent researchers have noted relationships between personality factors, especially personality disorders, and alcohol and drug addiction

(Khantzian and Treece 1985; Hesselbrock et al. 1985; Kosten et al.

1985; Cook and Winoker 1985). In a recent review of the literature on personality disorders and alcoholism/drug abuse, Grande

(1984) reported that from 75 to 80 percent of the studies surveyed

showed a positive association among the three conditions. He

87
concluded that a common etiological matrix predisposes one to behaviors that are diagnostic of the three conditions. The personality factors that appear central to the three conditions were:

Impulsivity, failing to inhibit behavior that previously led to

negative consequences, and placing value on immediate drug effects

(e.g., intoxication) over long-term consequences (e.g., liver

damage).

A number of recent studies have pointed to genetic factors in

personality. For example, Bouchard (1984) found that twins reared

apart had substantial similarities in personality. In particular,

personality characteristics such as introversion-extraversion,

impulsiveness, dominance, and flexibility showed high

heritabilities.

PROBLEMS IN ASSESSING PERSONALITY CHARACTERISTICS

Part of the reason for the generally poor showing of personality

factors in substance abuse is that rigorous longitudinal personality research is extremely difficult to conduct. Research examining the premorbid personality of alcohol or drug abusers has been

marked with numerous methodological problems. For example, it is

difficult to obtain an accurate premorbid picture of personality

characteristics using only measures administered at a single point

in time during the adult years. Retrospective research designs do

not allow us to know what the individual personality was like prior to the abuse. Additionally, measuring personality during an

episode of alcohol- or drug-abusing behavior is fraught with problems, since the instruments are likely to reflect situational

problems in addition to other personality factors.

In contrast, prospective studies in which personality factors are

measured early in the individual's life and followed up after the

addictive disorder has developed have been rare and problematic.

Also, they have been hindered by the scarcity of standardized

measures applicable to both adolescent and adult subjects. Also,

longitudinal studies measuring preaddiction personality characteristics are problematic in that, even if it were possible to

conduct prospective studies, there are few reliable and valid

personality measures that would provide usable information across

time.

Several studies have employed objective personality measures

(e.g., the Minnesota Multiphasic Personality Inventory (MMPI)) and

found personality characteristics associated with later addiction

(Hoffmann et al. 1974; Kammeier et al. 1973; Loper et al. 1973).

PERSONALTY AND ALCOHOL AND DRUG ABUSE

The salience of personality factors in alcohol- and drug-abusing

populations is well documented. A recent review of the MMPI

research in alcohol- and drug-abusing populations (Graham and

Strenger, in press) shows that the extensive use of the MMPI in

predicting alcohol and drug abuse problems results from its

88
considerable power to differentiate these individuals in clinical

settings. Several MMPI indices have been found to be successful

at detecting alcohol and drug abuse problems.

A large number of studies using the MMPI have found a strong association between personality factors and addiction. These studies

reported personality correlates of addiction as measured through

MMPI clinical scales, profile patterns, and special scales developed to assess patterns of addiction. An overview of MMPI findings in addictive behavior documents the relationship between

measured personality characteristics and addiction.

Early work on MMPI Scale 4 (Psychopathic Deviance) documents the

relative elevation of this scale among groups of alcoholics

(Hewitt 1943; Graham, unpublished manuscript; Button 1956; Hoyt

and Sedlacek 1958; MacAndrew and Geertsma 1963; MacAndrew 1978).

Several MMPI code types have been related to patterns of addictive

behavior (Gilberstadt and Duker 1965; Marks and Seeman 1963;

Schroeder and Pierce 1979).

Several studies have documented that MMPI profile characteristics,

found through multivariate clustering methods, are associated with

addictive disorders (Goldstein and Linden 1969; Whitelock et al.

1971; Nerviano and Gross 1983).

Special scales for assessing addiction patterns have been developed. The most promising of these is the MacAndrew Scale

(MacAndrew 1965; MacAndrew 1967; MacAndrew 1979; MacAndrew 1981;

Sher and McCrady 1984; Schwartz and Graham 1979).

In summary, research on alcohol- and drug-abusing populations with

the MMPI has shown several MMPI-measured personality characteristics to be associated with the manifestation of substance abuse.

It is probable that some aspects of this characteristic personality pattern are reactive to the disorder. However, the available

evidence suggests that certain personality characteristics probably precede the development of the disorder.

The MMPI is being restandardized at this time by James Butcher

(University of Minnesota), Grant Dahlstrom (University of North

Carolina), and Jack Graham (Kent State University) in order to

provide more relevant contemporary norms with a revised and expanded item pool that reflects more substantially the clinical

problems currently being encountered.

With regard to assessment of problems of addiction, a number of

new items dealing with alcohol and drug abuse (including prescription medications were included alona with a number of items dealing with treatment potential and comclipliance. In the Adult Version

of the MMPI, the 154 new experimental 

several areas of psychopathology not well represented in the original version of the test. In addition, a number of items were

included that showed promise for measur

items were added to assess

ing treatment amenability

89
and change. These additional items were selected through a broad

sampling of views of MMPI experts in order to determine needed

coverage in other content domains.

Several studies are presently under way to evaluate the effectiveness of the revised version of the MMPI with alcohol- and drugabusing populations. McKenna and Butcher (in preparation) have

conducted an extensive study of approximately 1,300 alcoholics and

drug abusers at the Hazelden Center in Centre City, MN. The performance of this population on the revised version of the MMPI was

compared to that of a sample of abusers from the same center 10

years before (McKenna and Pickens, unpublished manuscript). The

study demonstrated the continuity of the MMPI for assessing alcohol and drug abuse personality factors. In the future, the experimental items on the revised version of the MMPI will be used to

determine if alcohol and drug abuse problems can be more accurately detected with a revised addiction scale.

Adler and Butcher (in preparation) have begun an extensive study

of personality factors in alcohol- and drug-abusing adolescents.

This study is aimed at exploring personality factors noted in

early involvement with drugs and alcohol. Information related to

the actuarial description of MMPI alcohol and drug problem types

is being collected. The revised MMPI item content, relevant to

assessment of adolescent problem behavior, will be used to develop

an adolescent addiction proneness scale.

SUMMARY

In spite of the fact that past research has not found a unitary

concept of an "alcoholic personality," personality factors have

been found to be important in the development of alcohol abuse

disorders. Personality characteristics measured by the MMPI, particularly the Pd scale and the MAC scale, have been shown to be

related to the development of alcohol abuse disorders. Research

is currently under way to explore the ability of the revised version of the MMPI to detect and describe problems of alcohol abuse.

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Fox, S.W., ed. Individuality

Button, A.D. A study of alcoholics with the MMPI. Quarterly

Plenum Press, 1984.

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Cook B.;and Winoker,G. A family study of familial positive vs.

familial negative alcoholics. J Nerv Ment Dis 173:175-178,

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Gilberstadt, H., and Duker, J.A. A Handbook for Clinical and

Actuarial MMPI Interpretation. Philadelphia: Saunders, 1965.

Goldstein, S.G and Linden. J.D. Multivariate classification of

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Graham, J.R., and Strenger, V.E. MMPI characteristics of

alcoholics: A review. J Consult Clin Psychol, in press.

Grande, T.P.; Wolf, A.W.; SChubert, D.S.P.; Patterson, M.B.; and

Brocco, K. Associations among alcoholism, drug abuse, and

antisocial personality: A review of literature. Psychol Rep

55:455-474, 1984.

Gustafson, A., and Gustafson, Z.B.

London: Hodder & Stoughton, 1888.

The Foundations of Death.

Hesselbrock, M.N.; Meyer; R.E.; and Keener, J.J. Psychopathology

in hospitalized alcoholics.

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Arch Gen Psychiatry 42:1050-1055.

Hewitt, C.C. A personality study of alcohol addiction. Quarterly

Journal of Studies on Alcohol 4:368-386, 1943.

Hoffman, H.; Loper, R.G.; and Kammeier, M.L. Identifying future

alcoholics with MMPI alcoholism scales.

Studies on Alcohol 35:490-498, 1974.

Quarterly Journal of

Hoyt, D.P.and Sedlacek, G.M. Differentiating alcoholics from

normals and abnormals with the MMPI. J Clin Psychol 14:69-74,

1958.

Jellinek, E.M. The Disease Concept of Alcoholism. New Haven,

CT: College and University Press, 1960.

Kammeier, M.L.; Hoffmann, H.; and Loper, R.G. Personality characteristics of alcoholics as college freshmen and at time of

treatment.

1973.

Quarterly Journal of Studies on Alcohol 34:390-399,

Khantzian, E.J., and Treece, C. DSM-III psychiatric diagnosis of

narcotic addicts: Recent findings. Arch Gen Psychiatry

42:1067-1071, 1985.

Kosten, T.R.; Rounsaville, B.J.; and Kleber, H.R. Parental alcoholism in opioid addicts. J Nerv Ment Dis 173:461-469, 1985.

Langhorne, J., and Langhorne, W., trans. Plutarch's Lives.

Ithaca, NY: Andrus, Gauntlett & Company 1853.

Loper, R.G.; Kammeier, M.L.; and Hoffmann, H. MMPI characteristics of college freshmen males who later became alcoholics. J

Abnorm Psychol 82:159-162, 1973.

MacAndrew,C. The differentiation of male alcoholic outpatients

from non-alcoholic psychiatric patients by means of the MMPI.

Quarterly Journal of Studies on Alcohol 26:238-246, 1965.

MacAndrew, C. Self-reports of male alcoholics: A dimensional

analysis of certain differences from nonalcoholic male psychiatric outpatients. Quarterly Journal of Studies on Alcohol

28:43-51, 1967

MacAndrew, C. Women alcoholics' responses to Scale 4 of the MMPI.

J Stud Alcohol 39:1841-1854, 1978.

MacAndrew, C. MAC scale scores of three samples of men under

conditions of conventional versus independent scale administration. J Stud Alcohol 40:138-141, 1979.

MacAndrew, C. What the MAC scale tells us about men alcoholics:

An interpretive review. J Stud Alcohol 42:604-625, 1981.

MacAndrew, C., and Geertsma; R.H. An Analysis of responses of

alcoholics to Scale 4 of the MMPI. Quarterly Journal of Studies

on Alcohol 24:23-38, 1963.

Marks, P., and Seeman, W. The Actuarial Study of Abnormal

Personality. Baltimore: Williams & Wilkins, 1963

91
Nerviano, V.J., and Gross, H.W. Personality types of alcoholics

on objective inventories. J Stud Alcohol 44:837-851, 1983.

Schroeder, D.J., and Pierce,D.C. A comparison of MMPI two-point

codes in four alcoholism treatment facilities.

35:656-663, 1979.

J Clin Psychol

Schwartz, M.F., and Graham, J. Construct validity of the

MacAndrew Alcoholism Scale.

1095, 1979.

J Consult Clin Psychol 47:1090-

Sher, K.J., and McCrady, B.S. The MacAndrew Alcoholism Scale:

Severity of alcohol abuse and parental alcoholism. Addict Behav

9(1):99-102, 1984.

Sutherland, E.H.; Schroeder, H.G.; and Tordella, C.L. Personality

traits and the alcoholic: A critique of existing studies.

Quarterly Journal of Studies on Alcohol 11:547-561, 1950.

Syme, L. Personalty characteristics the alcoholic: A critique of current studies. Quarterly Journal of Studies on

Alcohol 18:288-302, 1957.

Whitelock, P.R.; Overall, J.E.; and Patrick, J.H. Personality

patterns and alcohol abuse in a state hospital population. J

Abnorm Psychol 78:9-16, 1971.

AUTHOR

James N. Butcher, Ph.D.

Department of Psychology

University of Minnesota

N428 Elliott Hall

75 East River Road

Minneapolis, MN 55455

92
Individual Differences in Drug

Response

James R. Wilson

INTRODUCTION

In mainstream psychology, it is not yet quite proper to hypothesize that genetics may contribute something to behavior. It does

not seem to be illegal to do so, merely indecent. This remnant of

radical behaviorism is still with us and still influential. However, the constraints on thought of considering only environmental

causation are being loosened, and some of us can admit, even in

public, that we are behavioral geneticists by trade.

The term behavior(a1) genetics (BG) may go too far the other way.

Do we now claim that all behavior is to be traced to genetics and

only genetics? I think the answer is "no." Of the hundred or so

behavioral geneticists I know, all seem to believe in the existence of the environment. In fact, genetically informative experimental designs are often environmentally informative as well, at

least in the sense that the proportion of variance attributable to

environmental factors is routinely estimated from BG designs.

In alcoholism research, there is persuasive evidence from Kaij

(1960; Kaij 1972), Goodwin et al. (1973; Goodwin et al. 1974;

Goodwin et al. 1977). Schuckit (1980; Schuckit 1981; Schuckit

1984; Schuckit 1985), Schuckit and Rayses (1979). Schuckit et al.

(1985), Cloninger et al. (1979; Cloninger et al. 1981), and others

that genetic variation contributes to the expressed variation in

alcohol abuse and/or alcoholism. The mechanisms that mediate

vulnerability to alcoholism may include differential sensitivity

or differential development of acute tolerance to alcohol, with

the supposition that those relatively insensitive to alcohol would

be at greater risk for increasing the amount they imbibe, thereby

increasing their risk for alcohol abuse.

The present paper will report on some of the large individual differences in sensitivity to ethyl alcohol from an ongoing BG study.

Though genetic and environmental parameter estimation will have to

await completion of data collection (in about 1 more year), this

paper will describe the research design used in the study. It is

93
important to note that similar strategies may be employed in the

study of individual differences in response to a variety of drugs.

METHODS

To further our understanding of the genetic architecture that

might be involved in the development of substance abuse, the present study is recruiting "normal drinkers" in subject pairs from

the following groups: 50 pairs monozygotic (MZ) twins (withinpair differences are environmental); 50 pairs dizygotic (OZ) twins

(differences are both genetic and environmental); 50 pairs nontwin

siblings (to test "special twin environment"); 50 pairs unrelated,

reared in the same family (adoptees) (common family environment;

no genetic variance in common); 30 retest subjects (to estimate

repeatability of tests); and 20 placebo controls (to estimate

practice/fatigue effects). Thus, upon completion of the study,

450 individuals will have been tested. At present, individual 12-

hour alcohol tests have been administered to over 300 persons, and

computer files exist with over 1,000 individual measurements for

290 of these people.

Estimation of various genetic and environmental parameters underlying responses to alcohol is facilitated by this experimental

design. For example, an MZ twin pair shares all genes plus common

family environment. Thus, the degree to which members of a pair

are alike reflects these components; the degree to which they are

unlike must be attributed to aspects of the environment which have

been different for members of the pair. The adoptee pairs, on the

other hand, have no genetic variance in common but, having been

reared in the same home, may resemble each other due to common

environmental influence. For pair resemblances in each group,

intraclass correlations (t) are computed for measures that have a

continuous or quasi-contiiiuous distribution. Using Falconer's

(1981) method as an example, heritability (broad sense) for a

trait may be estimated by doubling the difference between the MZ

and DZ ts. This follows from:

In practice, the genetic and environmental parameter estimates are

obtained by using information from all groups simultaneously and

using iterative, maximum-likelihood statistical packages such as

LISREL or MINUIT on a high-speed computer.

In addition to screening prospective participants for the genetic

relationships listed above, volunteer subjects must also meet the

following criteria: (a) report that they drink alcohol at least

once per month; (b) report no alcohol or drug abuse problems; and

94
(c) report no medical contraindications to dosing with alcohol.

The subjects are asked to report to the testing laboratory at

8 a.m., with the expectation of remaining until 8 p.m. A summary

of the testing day is shown in table I. Three test sessions were

completed prior to alcohol dosing (0.8 gm/kg), and three postalcohol test sessions were completed while blood alcohol level

(BAL) was held near 100 mg/dl for 3 hours via supplemental alcohol

doses.

TABLE 1. Summary of the testing day

Time Activity

0800 Interview; Raven and Vocabulary tests; light breakfast

0900 Test Session 1 (Pre-1)

1000 Test Session 2 (Pre-2)

1030 Cortical evoked response (CER baseline)

1045 Test Session 3 (Pre-3)

1115 Alcohol dose (0.8 gm ethanol/kg body weight)

1140 Test Session 4 (Post-l)

1220

1240

1250

1340

1350

1420

1450

1630

1640

1710

2000

Cortical evoked response (CER sensitivity)

Supplemental alcohol (to hold 100 mg/dl BAL)

Test Session 5 (Post-2)

Supplemental alcohol

Test Session 6 (Post-3)

Lunch in the laboratory

Subject rests; tester scores and enters dat a

Cortical evoked response (half-peak BAL)

Test Session 7 (half-peak BAL)

Subject rests

Subject leaves, if BAL < 20 mg/dl

For most subjects, this schedule is quite accurate. However,

given individual differences in metabolic clearance rates for

alcohol, there is variability in time for the half-peak BAL tests

and for being allowed to leave the laboratory.

The measurements taken during each test session included: Body

temperature, systolic blood pressure, diastolic blood pressure,

pulse rate, the Body Sway (Eyes Open) Test, the Body Sway (Eyes

Closed) Test, the Hand Steadiness Test, the Sequence Memory Test

(Simon game), the Pursuit Rotor Test (hand-eye coordination), the

Visual Acuity Test (Snellen), the Perceptual Speed (Written) Test,

the Cancellation Speed Test (clerical speed), the Sentence Completion Test (logic), the Card Rotations Test (spatial ability), the

Reaction Speed (Written) Test, the Block Rotations Test (spatial

ability), reaction and movement time (1 light, 10 trials), reaction and movement time (4 lights, 10 trials), reaction and

movement time (8 lights, 10 trials), the Rail-Walking Test, the

Dowel-Balancing Test, Space Armada game score, and the Profile of

95
Mood States Test. Test descriptions and procedures are discussed

more fully in Wilson and Plomin (1985).

RESULTS AND DISCUSSION

For the present study, the administered alcohol dose was meant to

bring BAL to 100 mg/dl, on average. The mean BAL curve is shown

in figure 1. As can be seen, the obtained average is nearer 95

mg/dl. Also, there are wide individual differences in peak BAL

(from 70 to 130 mg/dl), apparently as a result of differences in

rate of absorption, rate of clearance, and volume of distribution.

FIGURE 1. Mean blood alcohol level (BAL)

NOTE: The initial dose, given in the 15 minutes prior to Time 0, was 0.8 gm

ethanol/kg body weight. Small "topping up" doses were given at 60 minutes

and 120 minutes in an attempt to maintain the BAL of each individual near

the initial peak BAL for 3 hours, for tests of acute behavioral tolerance

to ethanol (ABTE).

However, the "topping up" doses are meant to keep an individual as

near his/her initial peak BAL as possible, so that the initial

effects of alcohol can be compared to the effects after 3 hours at

about 100 mg/dl BAL in order to measure acute behavioral tolerance

to ethanol (ABTE) (Wilson et al. 1984).

96
An individual BAL curve is shown in figure 2. The 0.8 gm/kg dose

of alcohol was administered during the 15 minutes prior to Time 0

on the graph. For most people, this amounts to 4 to 6 bar drinks

taken during a 15-minute period. BAL estimates, derived from

breath samples with an Intoxilyzer, are taken every 10 minutes for

3 hours and every 30 minutes thereafter. Test Session 4 (Post-1)

begins 10 minutes after the end of dosing and, for most people,

spans the later parts of the absorption phase, up to and including

the initial peak BAL. "Topping up" doses are administered at 60

minutes and again at 120 minutes to try to maintain a relatively

constant BAL for a period of 3 hours. The Post-2 and Post-3 tests

follow 10 minutes after each "topping up" dose. From these

curves, several parameters are derived, including: Time-to-peak

BAL (measure of absorption time), peak BAL (measure of volume of

distribution), Beta60 (linear rate of clearance), and relative

volume of distribution (Widmark r). Linear extrapolation of the

Beta60 (Wilson and Erwin 1983) line to the Y-axis yields what

Widmark called the "instantaneous dosage" estimate (C0). I am

FIGURE 2. An individual blood alcohol level (BAL) plot

NOTE: From the BAL data from each individual, the linear clearance rate (Beta60),

the "instantaneous dosage” (C0), and the relative volume of distributlon

(Widmark r) were estimated.

97
currently attempting to refine this estimate, using the area under

the curve rather than the somewhat exaggerated area Widmark used

(Wilson, in press). A better instantaneous dosage estimate will

yield better estimates for the apparent volume of distribution and

the Widmark r.

A plot of mean body sway (eyes closed) across the seven test sessions is shown in figure 3. Test session is shown on the abscissa, and mean score or measurement is shown on the ordinate. The

placebo control group mean (n=21) is plotted with pluses, and the

alcohol group (n=269) is plotted with squares. Consonant with the

literature, there is an average decrement in performance, as indicated by the increase in sway after dosing. The mean change-score

at Test Session 4 (Post-1) is a typical indicator of sensitivity.

If performance improves from Test Session 4 (Post-1) to Test Session 6 (Post-3), the test shows acute behavioral tolerance effects

(ABTE). An immediate criticism, though, is that practice effects

might lead to the improvement. Therefore, for an estimate of

ABTE, we need to compare the slope of improvement in the experimental group with the slope of improvement in the control group.

FIGURE 3. Body Sway (Eyes Closed) Test

NOTE: Means and standard errors were computed from the reciprocal of inches of

sway for each individual, so more sway is lndicated by a lower score.

98
In practice, the relative sensitivity score for each person on

each test is determined by computing the standardized residual

from linear regression of each person's Post-1 score on his/her

baseline score (where the baseline score is an average of the Pre2 and Pre-3 scores) after correction for control group scores at

Post-1 and baseline. Then a computer can sort subjects on the

basis of sensitivity score, arranging subjects from most to least

sensitive on each function. This method of computing sensitivity

scores is based on a recommendation by Cohen and Cohen (1975), and

the methodology used is explained more fully in Nagoshi et al.

(1986). The method has several advantages over the difference

scores (pretest score minus posttest score) or ratio scores

(posttest/pretest), which have often been employed as a means of

taking into account the large preexisting individual differences

in abilities.

Figure 4 shows mean reaction time over the seven test sessions.

Mean sensitivity to alcohol on this function can be seen from the

increase in reaction time after dosing. What might be ABTE can

also be seen from the decrease in reaction time between the Post-1

and Post-3 tests while BAL has been held near 100 mg/dl. The

slope in this interval appears to be different from that for the

FIGURE 4. Reaction Speed Test (single stimulus light)

99
control group, so practice effects are not a likely alternative

explanation. In actuality, a relative ABTE score for each individual on each test is obtained by computing the standardized residual from linear regression of the Post-3 scores on the Post-l

scores after correction for the control group scores at Post-3 and

Post-l. This procedure is also explained more fully in Nagoshi et

al. (1986). Analogously, total tolerance ("delayed sensitivity")

is obtained as the standardized residual from regression of Post-3

scores on baseline and control group Post-3 and baseline scores.

Figure 5 shows mean pursuit rotor scores across the seven test

sessions. This test shows a strong practice effect, as can be

seen from the increasing scores for the control group. Despite

this practice effect, the sensitivity effect can be easily visualized from the drop in the mean score for the alcohol group at

Post-l testing. It is also clear that the minor improvement seen

at Post-3 testing is probably due to practice, not ABTE. Parenthetically, it may be noted that on this test (and most others),

the function beinq measured has recovered almost completely by

FIGURE 5. Pursuit Rotor Test

NOTE: A consistent affect of practice can be seem from the increase In scores

Over test sessions. The small increment in mean scores for the alcoholtreated group between Alc-1 and Alc-3 is not significant.

100
Post-4 testing, although BAL at this time for most people is still

typically about 50 mg/dl. This is another indicator of acute tolerance to ethanol, after possible practice effects are taken into

account.

The intent of the preceding figures was not to belabor the wellestablished fact that ethanol generally depresses function, but

rather to outline the methodology of obtaining standardized sensitivity and tolerance scores for individuals. These are the individual differences that will figure prominently in the planned

maximum-likelihood analyses to obtain genetic and environmental

parameter estimates of responses to alcohol. As indicated earlier, the study is not complete; therefore, these estimates cannot

be given now. However, some of the obtained individual differences will be highlighted below.

For example, table 2 (from the Hawaii Alcohol Study (Wilson et al.

1984)) describes the percentage of individuals showing an improvement rather than a decrement during the sensitivity testing

period. These numbers are simply the percentages of subjects who

improved (from their baseline performance) during testing after

alcohol dosing. No correction for practice has been made. While

some of these tests show practice effects, others do not. In this

latter group, it is apparent that gains from practice are possible

even while at 100 mg/dl BAL, and the expectation of a performance

decrement does not hold for all individuals.

TABLE 2. The percentage of Subject who show improvement in test

score during alcohol-sensitivity testing

Test Percent

Dowel-Balancing 30

Rail-Walking 19

Body Sway (Eyes Open) 41

Body Sway (Eyes Closed) 26

Reaction Time 34

Sentence Completion 21

Card Rotations 30

Cancellation 19

Colorado Perceptual Speed 4

Hand Steadiness 2 0

Tapping Speed 3 3

Iconic Memory 34

Pursuit Rotor 1 7

Apple Invader 2 8

SOURCE: Wilson et al. 1984. Copyright 1984, the American Medical Society on

Alcoholism and Other Drug Dependencies, the Research Society on

Alcoholism.

101
Table 3 shows the proportion, by test, of the alcohol-treated

group which equalled or exceeded the average of the placebo control group at Test Session 6 (Post-3). If a BAL of about 100

mg/dl for 3 hours had no effect, we would expect the proportions

to be about 50 percent. As they stand, they indicate the percentages, by test, of people at 100 mg/dl who performed the test as

well as an average sober person who also had five practice trials

during the preceding several hours. These results exemplify the

difficulty of discriminating those with a BAL of 100 mg/dl from

those with a BAL of zero via roadside sobriety tests.

TABLE 3. Proportion of the alcohol-treated group which equalled

or exceeded the placebo control group mean at Test

Session 6

Measure Percent

Systolic blood pressure

Diastolic blood pressure

Pulse rate

Visual Acuity Test

Rail-Walking Test

Dowel-Balancing Test

Pursuit Rotor Test

Hand Steadiness Test

Space Armada

Body Sway (Eyes Open) Test

Body Sway (Eyes Closed) Test

Perceptual Speed Test

Cancellation Speed Test

Sentence Completion Test

Card Rotations Test

Block Rotations Test

Reaction Speed (Written)

61 (lower)

58 (lower)

39 (lower)

47

27

18

31

40

29

41

29

29

43

53

43

34

49

Figures 6 and 7 have two purposes. First, they illustrate, using

frequency histograms, the visual appearance of two of the obtained

score distributions which had statistically different means.

Second, they describe two individuals within the histograms who

responded very differently at different stages of alcohol

metabolism.

In figure 6, for all three panels, the rail-walking score is on

the abscissa, and the frequency or proportion of people obtaining

that score is on the ordinate. The lowest panel is a histogram of

score frequency at baseline (prealcohol). The middle panel is a

frequency plot of scores immediately after alcohol (sensitivity

testing). Both an increase in dispersion and a relatively small

shift in mean can be noted. The top panel is a frequency plot

102
FIGURE 6. Frequency histograms of rail-walking scores from the

alcohol-treated group

NOTE: The bottom panel includes baseline (prealcohol) scores, the center panel

includes scores obtained 10 to 30 minutes after alcohol doslng (sensitivity

testing), and the top panel includes scores taken after BAL was maintained

near 100 mg/dl for 3 hours. (See text for explanation of X end 0 symbols.)

103
FIGURE 7. Frequency histograms for Body Sway (Eyes Closed) Test

NOTE: The panels are arrayed as in figure 6.

0 symbols.)

(See text for explanation of X and

104
after 3 hours at a BAL of about 100 mg/dl (for tolerance estimates). Note the individuals marked X and 0 who were chosen as

being near the mean at baseline. During sensitivity testing

(middle panel), X proves to be very sensitive, while 0 is not.

During ABTE testing, X has recovered function, and 0 is actually

above his/her baseline score.

In figure 7, a similar comparison of score distributions before

and after alcohol is shown for body sway. Again, note the increase in dispersion after dosing and the differential shift within the distributions of individuals X and 0. Body sway shows

little tolerance effect and thus may be a useful roadside test.

Of course, some apparatus for measurement accuracy may be needed,

and comparison 0 BAL sway scores are not usually available.

SUMMARY AND CONCLUSIONS

In conclusion, there seem to be large, pervasive individual differences before and after dosing with ethyl alcohol. As estimates

for sensitivity and tolerance to alcohol imply a change from a

previous measurement, regression procedures were used to obtain

sensitivity and acute tolerance scores for each subject on each

test. It seems likely that this regression procedure would be

equally applicable for estimation of sensitivity and tolerance to

any other drug.

With the quantitative behavioral genetic design being employed, it

will be possible to partition the sensitivity and tolerance variances into genetic and environmental components. These estimates

of the relative contributions of genes and environment should

prove useful in risk estimates of alcohol abuse for individuals

and perhaps will facilitate attempts to ameliorate the effects of

alcohol abuse.

It is encouraging that NIDA is focusing some of its attention

toward the study of biological vulnerability to drug abuse. The

careful use of quantitative behavioral genetic designs in studies

of drug use and drug response will, when such designs are feasible, yield a more complete picture of the genetic and environmental bases for drug abuse than would studies which do not include a

genetic component. Admittedly, cohort differences in drug availability may make parent/offspring designs unfeasible (i.e., the

drug may not have been available a generation ago). However,

parent/offspring designs which involve a correlated character

(e.g.,) sensation seeking) or a biochemical measurement may prove

useful.For example, the "high" stimulated by some drugs may

reflect adrenal medullary activation, and this could be assessed

by measurement of blood epinephrine and norepinephrine. Also,

behavioral genetic designs which involve twins, siblings, and

adoptees should be directly applicable to studies of drug use and

effects, as the subjects are either the same age or can be chosen

within certain age limits. These designs would largely avoid

undesired cohort effects, such as the unavailability of certain

105
drugs a generation ago, yet would yield estimates of genetic and

environmental influences on drug use or drug response.

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Wilson, J.R. Triangularizing the alcohol metabolic plot improves

parameter estimation. Alcoholism, in press.

Wilson, J.R., and Erwin, V.G. Rate of alcohol metabolism: Do not

"correct" the B60 estimate for comparisons among individuals or

groups. J Stud Alcohol 44:1093-1096, 1983.

106
Wilson, J.R., and Plomin, R. Individual differences in sensitivity and tolerance to alcohol. Soc Biol 32:162-184, 1985.

Wilson, J.R.; Erwin, V.G.; McClearn, G.E.; Plomin, R.; Johnson,

R.C.; Ahern, F.M.; and Cole, R.E. Effects of ethanol: II.

Behavioral sensitivity and acute behavioral tolerance.

Alcoholism: Clin Exp Res 8:366-374, 1984.

ACKNOWLEDGMENTS

The support of NIAAA grant AA-03527 and Biomedical Research

Support grant RR-07013-20 is gratefully acknowledged. In addition, it is a pleasure to acknowledge the fine collaboration on

this project of Professor V. Gene Erwin, School of Pharmacy,

University of Colorado; Professor Robert Plomin, who is at the

Center for Advanced Study in the Behavioral Sciences in Palo Alto,

CA, this year, and then will be taking up his new position at

Pennsylvania State University; and Dr. Craig Nagoshi, who is a

NIDA postdoctoral fellow working on the project.

AUTHOR

James R. Wilson, Ph.D.

Institute for Behavioral Genetics,

Department of Psychology, and

Alcohol Research Center

University of Colorado

Boulder, CO 80309-0447

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The Role of Psychopathology in the

Familial Transmission of Drug Abuse

Bruce J. Rounsaville

INTRODUCTION

Since there is some evidence that alcoholism and/or drug abuse are

transmitted in families (e.g., Goodwin 1976), the next question

is, What is being transmitted? To identify the mechanism of

transmission, two models have been formulated. In the first, the

familial pattern of inheritance may be the result of drug-related

factors (i.e., related to mechanism of action or metabolism of the

substance). In this case, the familial-transmitted factor may be

broad (e.g., especially high level of positive reinforcement from

psychoactive substance use) or narrow (e.g., special sensitivity

to specific classes of drugs such as sedatives or stimulants).

The alternative hypothesis is that familial clustering is the result of factors not directly related to drug use. For example,

drugs may be more accessible to individuals with drug-abusing parents, thereby making it more likely that they will also use drugs.

Another possible class of familial-transmitted factors that may

predispose to substance abuse is psychopathology. In this case,

symptoms of another psychiatric disorder (e.g., depression) predispose an individual to drug abuse. For example, drug abuse

may arise from a need to use drugs to reduce anxiety and/or

depression.

Identification of the familial transmission mechanism of drug

abuse, however, does not resolve the issue of the relative contribution of genetic and environmental factors in the etiology of the

disorder; both biological and/or behavioral factors may contribute

to the mechanisms described above. For example, if drug abuse

arises from self-medication of depression, then it would be important to determine the etiology of the depressive symptoms.

The purpose of this chapter is to describe evidence that might

suggest that psychopathology is being transmitted in the families

of substance abusers and that it is an underlying cause of some

forms of substance abuse. Other chapters will cover evidence for

more direct familial predispositions to substance abuse per se.

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In considering the different models for familial transmission of

substance use disorders, it should be noted that (a) the models

are not mutually exclusive, so there can be multiple familialtransmitted pathways to substance abuse (e. g., depression plus or

minus variants in opioid receptors), and (b) the population of

substance abusers is likely to be heterogenous, so, for example,

some may have become substance abusers because of familial predisposition to antisocial personality, others in relationship to a

familial predisposition to depression, and still others with no

familial predisposing factors whatsoever (Rounsaville et al.

1982a).

To support the hypothesis that psychiatric disorders are transmitted in the families of substance abusers, and this transmission is

related to the substance abuse, there should be evidence of several kinds: (a) increased rates of psychiatric disorders in

substance abusers; (b) increased rates of substance abuse in individuals with other psychiatric disorders; (c) increased rates of

psychiatric disorders in the families of substance abusers and a

more than expected co-occurrence of the two types of disorders

within the families; and (d) increased rates of substance abuse in

the families of those with the hypothetically related psychiatric

disorders, showing a more than expected co-occurrence of the two

types of disorders in the same family members.

COEXISTENT PSYCHIATRIC DISORDERS IN SUBSTANCE ABUSERS

At present, the best information on associated psychopathology in

nonalcoholic substance abusers has been obtained with opioid

addicts. Since my research has also focused primarily on opioid

addicts, the present paper will, to a large extent, focus on this

disorder. It should be noted, however, that problems and strategies encountered in the study of opioid addicts will be applicable

to the study of other types of drug abuse as well.

In research evaluating psychopathology in abusers of different

classes of psychoactive substances, it is sometimes assumed that

the associated psychopathology will be different for various drug

classes. Moreover, many studies evaluate familial transmission of

a predisposition to specific forms of substance abuse (e.g., cocaine abuse). This implies that transmission may be distinct for

the different classes of drugs, making it harder to evaluate

whether a more general transmission of substance abuse is taking

place. In fact, polysubstance abuse is the rule rather than the

exception, a finding that broadens the scope of research questions

but also reduces the definitiveness of findings.

To determine the specific psychiatric disorders that are most

prevalent in the families of opioid abusers, two studies evaluating psychiatric disorders in treated opioid addicts, using

structured and specified diagnostic criteria, were recently

completed. In the New Haven study of 533 treated opioid addicts

(Rounsaville et al. 1982b), the three disorders covered by

Research Diagnostic Criteria with rates far in excess of those

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found in the community were Major Depression (53.9 percent),

Antisocial Personality (26.5 percent), and Alcoholism (34.5 percent). These findings are mirrored by a Cambridge, MA, study of

133 opioid addicts, using DSM-III criteria (Khantzian and Treece,

in press), which found rates of 56 percent for Depression and 35

percent for Antisocial Personality.

Because these rates were derived from treatment-seeking groups,

they may be artifactually high (i.e., having two disorders may

predispose to treatment seeking). To evaluate this possibility,

the New Haven study also evaluated a community sample of nontreatment-seeking opioid addicts and found that only Major

Depression showed a rate difference (Rounsaville and Kleber

1985). While treatment-seeking addicts were more likely to be

depressed than community addicts, even the latter group showed

higher rates of Major Depression than expected from a community

survey (Weissman et al. 1978).

Because treatment-seeking groups are special in many ways, the

importance of community data is high. Unfortunately, community

surveys have not provided useful data about the coexistence of

opioid addiction and psychopathology. The most definitive community findings on rates of substance use have been obtained from

National Institute on Drug Abuse (NIDA)-sponsored household

(Miller et al. 1983) and high school (Johnston et al. 1983)

national surveys which have focused exclusively on quantity and

frequency of drug use. These studies are of little help in the

study of either substance abuse or coexisting psychopathology,

because they do not determine whether the patterns of drug use

would allow diagnosis of a substance use disorder, nor do they

evaluate associated psychopathology.

The major study which has evaluated both substance use disorders

and psychopathology in general community surveys is the Epidemiology Catchment Area (ECA) Study (Myers et al. 1984; Robins et al.

1984). While this is a landmark study in which thousands of subjects were interviewed at multiple sites across the United States,

the findings are of limited use for evaluating coexistent psychopathology in substance abusers for several reasons. First, while

overall lifetime rates of substance use disorders were over 5 percent, these rates were largely accounted for by marijuana, with

rates for opioid and cocaine abuse/dependence at less than 0.5

percent each. Hence, out of a sample of over 9,000 subjects, the

numbers of opioid and cocaine abusers were less than 60 and less

than 30, respectively. Second, the National Institute of Mental

Health (NIMH) Diagnostic Interview Schedule (Robins et al. 1981)

was used. This instrument takes special care to insure that

psychiatric symptoms were not caused by psychoactive substance

use, thereby discounting the symptoms of psychiatric disorders

that occurred during periods of substance abuse. Because many

substance abusers never have a sustained drug-free period, diagnosis of coexistent psychopathology was not possible using this

instrument without post hoc recoding of the data. Third, there

was no special attempt to assure subjects of the confidentiality

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of their replies regarding use of psychoactive substances. While

the NIDA-sponsored household survey preserved the confidentiality

of subjects both by not recording names on answer sheets and by

having the subjects themselves fill out answers to questions

rather than having the interviewer fill out the questionnaires

(Miller et al. 1983), none of these special precautions were taken

in the ECA study. Hence, there is the strong possibility that

rates of substance use disorders were underreported. This possibility is especially likely considering the finding that lifetime

rates of some substance use disorders actually dropped at 6-month

and 1-year reinterview.

COEXISTENT SUBSTANCE ABUSE IN ALCOHOLIC, ANTISOCIAL PERSONALITY,

AND DEPRESSED PROBANDS AND THEIR FAMILY MEMBERS

The evaluation of psychiatric disorders in treated opioid addicts

suggests that the disorders most likely to be transmitted are

alcoholism, antisocial personality, and depression. To date,

studies of opioid addiction in populations with diagnoses of

depression, antisocial personality, and alcoholism have been

sparse. Before reviewing the evidence, it is important to note a

fundamental problem which places major limitations on the types of

research designs which can be used to assess familial transmission

of psychopathology and opioid abuse--that is, exposure of the general population to heroin and other illicit opioids, even in recent years but especially over 20 years ago, has been relatively

rare. Substance use disorders, unlike any other psychiatric disorders, have a known environmental agent which is necessary for

developing the disorder; namely, exposure to the abused substance.

For heroin, this means that only a small fraction of the population will place themselves at risk for having heroin addiction.

Findings from the National Household Surveys from 1972 to 1984

have reported that only 5 percent of young adults and 1.1 percent

of older adults had tried heroin even once (Miller et al. 1983;

Rounsaville 1985). Hence, even if those with other psychiatric

disorders, including depression, antisocial personality, and/or

alcoholism, had a coexistent predisposition to become a heroin

addict, only a small fraction of these groups are likely to have

ever allowed this predisposition to influence their lives, because

they were never exposed to the environmental agent of the disorder. This contrasts markedly with alcohol, which over 90 percent of the U.S. population has been exposed to at least once.

The importance of limited exposure to illicit opioids in evaluating the literature on other psychiatric disorders is that negative

findings from these studies are not necessarily a severe blow to

the hypothesis that underlying psychopathology is a familialtransmitted cause of heroin addiction. Studies of alcoholics tend

to show rates of abuse of other substances (including opioids)

higher than those expected from community levels (Grande et al.

1984; Hesselbrock et al. 1985). In addition, the preponderance of

evidence suggests that nonalcoholic substance abuse is found more

commonly than expected in those showing evidence of antisocial

personality (Grande et al. 1984). This has not been demonstrated

111
for samples of treated and community depressives (Helzer, in

press; Merikangas et al., unpublished).

There is little to review regarding findings which show excess

rates of psychiatric disorders in the families of opioid addicts

or excess rates of opioid addiction in the families of those with

other psychiatric disorders. In the latter case, the lack of evidence is most likely related to the very low community rates of

opioid addiction (less than 0.5 percent), so families of those

with other psychiatric disorders would be required to have massively increased prevalence of opioid addiction for a statistically significant association to be found. The remainder of this

chapter will be devoted to sorting through available research

strategies for evaluating psychopathology rates in families of

opioid addicts to obtain evidence that psychopathology is a

familial-transmitted cause of opioid addiction.

RESEARCH DESIGNS FOR STUDY OF FAMILIAL TRANSMISSION OF LINKED

PSYCHOPATHOLOGY AND OPIOID ADDICTION

In evaluating possible genetic transmission of opioid addiction

and/or associated psychopathology, there are three general types

of research designs available: Twin studies, adoption studies,

and family/pedigree studies. Twin studies are frequently presented as providing evidence for a genetic component to the illness

under study if it is shown that monozygotic twins have a higher

concordance for the disorder than dizygotic twins. However, as

Kidd and Matthysee (1978) have pointed out:

The major value of twin studies has been that the finding of discordant monozygotic twins allows one to reject the hypothesis of complete genetic determinancy...

The finding that monozygotic twins have a greater

concordance than dizygotic twins does suggest the

involvement of biologic factors. However, monozygotic

(MZ) twins may also have greater environmental similarities than dizygotic (DZ) twins. Thus, a greater MZ

concordance does not, in itself, allow rejection of

either a purely environmentalist hypothesis or a purely

biological hypothesis. (Kidd and Matthysee 1978,

p. 927)

Strong evidence for a genetic component of a disorder can be

obtained from adoption studies, which evaluate transmission of

disorders from parents to children who are separated from them at

birth. Hence, the excess of disorders in adopted children of biological parents with the disorder, in contrast to similarly adopted children of parents without the disorder, can most readily be

explained as being related to genetic transmission of risk for the

disorder.

Twin and adoption studies are absent in the study of opioid addiction or other illicit drug abuse. The major reason for this absence is, again, the relatively low prevalence of opioid addiction

112
or even exposure to abusable opioids in the general population.

This is particularly the case in the Scandinavian countries in

which the best twin and adoption registries have been kept.

Finding a sample of twins who have been exposed to opioids might

be feasible through a search of U.S. files of treatment-seeking

opioid addicts. However, as noted above, twin studies do not

really provide strong evidence for a genetic component of disorders. Moreover, twin studies tell nothing about the mode of

inheritance and only provide suggestive evidence that a disorder

is genetically transmitted.

The third study design available for evaluating transmission of

psychiatric disorders and opioid addiction is family/pedigree

studies. In these studies, families in which the disorder of

interest is present are found through identified family members

(probands) who have the disorder. All available relatives,

including first- and second-degree relatives, are evaluated using

either direct evaluation (e.g., direct interview) or the family

history method, in which the psychiatric histories of all family

members are obtained only from interviewed family members. Hence,

a psychiatric history is available on all family members, including those who are dead or otherwise unavailable for interview. In

order to reconcile divergent information from multiple informants,

a "best estimate" procedure is utilized whereby two independent

raters make a final diagnosis on the basis of all available information (including direct interview, interview of relatives, and

medical records). Following independent review of the same data,

differences between the two best estimate raters are themselves

reconciled.

Family/pedigree studies have a number of advantages. First, they

are comparatively feasible. Because families are identified

through probands who have the disorder of interest, it is possible

to identify relatively large numbers of families even when the

disorder under study is relatively rare in the general population.

This is clearly not the case with adoption and twin studies.

Second, it is possible to obtain relatively rich and up-to-date

information about probands and their families, because many family

members can be personally interviewed. Again, this contrasts with

many adoption and twin studies in which investigators are limited

to information available from medical records kept by adoption

agencies and/or records of criminality, alcoholism, or treatment

for psychiatric disorders maintained in the countries in which the

study is taking place. These older records contain incomplete and

variable amounts of information and are frequently inadequate for

determining whether subjects meet recently developed diagnostic

criteria for psychiatric disorders. Moreover, the possibility

that individuals with the disorder are not identified through a

search of public records (e.g., whether a family member was listed

with a Scandinavian temperance board) is reduced through direct

interview or the family history method. Third, and most importantly, while twin and adoption studies provide comparatively

little information about mode of transmission, these data can be

obtained from family and multigenerational pedigree studies.

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To evaluate familial transmission of psychiatric disorders that

may be associated with opioid addiction, family history data must

be collected from samples of opioid-addicted probands with and

without the trait being evaluated (e.g., depression and antisocial

personality) and from normal probands and/or those with other

psychiatric disorders but no evidence of opioid addiction (e.g.,

depression and antisocial personality). For transmission of associated psychiatric disorders to be a plausible model, it should

first be shown that (a) families of opioid addicts have an excess

of the associated disorders (e.g., antisocial personality, depression, and alcoholism), and (b) within the families of opioid

addicts, there is an association between the other psychiatric

disorders and opioid addiction or other addictive behaviors (i.e.,

family members with an addictive disorder also tend to have the

associated disorders). If these two conditions hold true, it is

then possible to evaluate transmissibility of the different disorders and the association of transmissibility of the disorders

using models developed by Reich et al (1979).

DESIGN OF THE FAMILY/GENETIC STUDY OF OPIOID ADDICTION

To pursue the hypothesis that opioid addiction is familial-transmitted through the mechanism of associated psychiatric disorders,

we have, over the past 3 years, been conducting a family study of

opioid addicts (Rounsaville, unpublished manuscript). The study

includes male and female subjects with opioid addiction and no

other psychiatric disorders, opioid addiction plus major depression, and opioid addiction plus antisocial personality. Alcoholism, while not examined separately, was associated with 40 percent

of the probands in this study and was evenly distributed across

cells. The age range of the proband sample was limited to 18 to

35 years, because the treated sample did not contain sufficient

numbers of those over 35 to allow cohort effects of a wider age

range to be taken into account. An attempt was made to interview

all first-degree relatives in the parental and sibling generations. Children were excluded because very few orobands reoorted

having children 16 years old or older. The direct interview

included the Schedule for Affective Disorders and Schizophrenia

(SADS) (Endicott et al. 1978) and the Family History Research

Diagnostic Criteria (Andreason et al. 1977). Family history data

were obtained for all first-degree relatives from all family

members who were interviewed. Diagnostic disagreements across

different sources of information were reconciled using the best

estimate procedure outlined above. The comparison sample consisted of data gathered from the families of normals and depressives. The disorders evaluated included (a) addictive behaviors

(defined both broadly and narrowly) and (b) psychiatric disorders

covered in the Research Diagnostic Criteria (RDC) (with a special

interest in depression and antisocial personality).

In the present study, it was assumed that opioid addicts are a

heterogenous group and that there may be numerous pathways to

addiction. If the associated psychiatric disorders play a major

role in the transmission of opioid addiction (or substance use

114
disorders), we would expect to see the following: (a) probands

with only a substance abuse diagnosis will have an excess of

addictive behaviors in their families but no excess of other disorders; (b) probands with both major depression and substance

abuse diagnoses will have an excess of both addictive behaviors

and depression but no other disorders in their families; and (c)

probands with both antisocial personality and substance abuse will

have an excess of addictive behaviors and antisocial personality

(but no other disorders) in their families.

Problems/Limitations With This Design

While the design of this study has many strengths listed above,

there are a number of practical and conceptual limitations as

well. It is difficult to evaluate the specific transmissibility

of opioid addiction, per se, because the parental generation was

much less likely to be exposed to opioids during the ages of 12 to

25, which is the time of greatest vulnerability to the disorder.

While specific categories of drugs abused by the siblings of the

addicts can be examined, studies are forced to evaluate transmission of broader categories of substance abuse. Hence, if a specific sensitivity to opioids is being transmitted, the data

currently available would not address this issue. Another difficulty in explaining the specific drug sensitivity hypothesis is

the fact that polysubstance abuse is the modal drug abuse pattern

of today. This sequential or simultaneous abuse of multiple

classes of drugs, in itself, suggests that traits being familialtransmitted are not narrowly related to the metabolism of any

particular drug.

The data from this type of study can never definitively rule in or

out genetic vs. environmental components of transmission of disorders in families. Although it is possible to evaluate the contribution of genetic (e.g., disorder in first-degree relatives)

and environmental elements (e.g., exposure to illicit substances

during teen years) using multiple threshold models, the results of

this type of model testing are seldom definitive.

Sophisticated model-fitting procedures are available for assessing

whether the transmission of the trait being studied within the

sample conforms to known mechanisms including single locus inheritance, polygenic inheritance, multilocus inheritance, etc. (Kidd

and Matthysee 1978). Likelihood ratios tests can be used to compare different hypotheses about the relationships of genotypes to

phenotypes. In practice, however, factors such as incomplete

penetrance and uncontrolled environmental influences usually make

it difficult to rule out any of the possible genetic mechanisms of

transmission of the trait. This is especially a problem if the

trait under study is transmitted in numerous different ways.

Hence, at best it is possible to rule out a few of the possible

modes of genetic transmission using data from family studies.

As a practical matter, when probands with psychiatric disorders

are being studied, it is difficult to secure the cooperation of

115
large numbers of family members. In the present study, only

around 1.5 first-degree relatives per proband were interviewed,

with similar results in studies of depressives (Weissman et al.

1982) and alcoholics (Cloninger et al., in press). Although

information from multiple informants greatly reduces the insensitivity of the family history method, direct interview of all relatives remains the most sensitive method for obtaining psychiatric

diagnoses. In such studies, however, it is important that interview status be entered as a covariate.

The effects of temporal trends and variable lengths of time at

risk must be considered in all analyses. Across families and

within families, different relatives will be in widely different

age ranges, thereby having different lengths of time at risk for a

psychiatric disorder. Hence, it might be anticipated that those

who are older would have higher risk for disorders than those who

are younger (Weissman et al. 1984). Despite this seemingly logical trend, there has been considerable evidence from community

studies that rates of substance use and other disorders (e.g.,

depression) are becoming more common in younger age groups

(Cloninger et al., in press; Klerman et al. 1985). To handle

these two conflicting trends related to cohort effects and time at

risk, age and year of birth must be included in all analyses.

FUTURE DIRECTIONS

The present study is currently in the phase of finalizing best

estimate diagnoses, and data analysis will begin shortly. To

maximize the scientific yield from the current study, it is important to: (a) obtain longitudinal information on the children of

the addicts in the sample, because they represent a group at high

risk for addictive behaviors, and (b) attempt to identify large,

informative multigenerational pedigrees within the addict population in order to take advantage of recent, exciting advances in

linkage techniques.

Study of Children at High Risk for Opioid Addiction

Because we have restricted the age range of the addict sample, the

ages of their children are relatively low, with half of the children aged six and under and only a small fraction being over 15

years of age. Hence, the great majority have not completed the

period of maximum risk for developing a substance use disorder.

We hope to evaluate these children at multiple time periods in

order to identify psychopathological, behavioral, environmental,

and biological precursors of developing a substance use disorder.

Evaluation of psychiatric disorders in children has been made more

feasible through the development of children's psychiatric interviews like the Kiddie-SADS (Chambers et al., in press).

Linkage Studies

In just the past few years, the number of identified markers on

the human genome has expanded tremendously based on the discovery

116
of restriction fragment length polymorphisms (RFLP) (Kidd 1982).

This has made it possible to pinpoint, in the case of single major

locus genetic transmission, the actual location of the gene responsible for conferring risk for a given disorder. These analyses are very sensitive to the definition of the syndrome used,

which is a major stumbling block for disorders with unclear boundaries, such as psychiatric disorders. The major focus of linkage

studies has been large, multigenerational pedigrees in which substantial numbers of individuals are positive and negative for the

trait under study. Participation In both diagnostic assessments

and donation of blood samples is needed from as many family members in the sample as possible. The discovery of such pedigrees

is a rare event, but this type of research is clearly needed in

the study of families of drug abusers.

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Onset of major depression in early adulthood: Increased familial loading and specificity. Arch Gen Psychiatry 41:1136-1143,

1984.

AUTHOR

Bruce J. Rounsaville, M.D.

Department of Psychiatry

Yale University School of Medicine

904 Howard Avenue, Suite 2-E

New Haven, CT 06519

119
Methodological Issues in Family,

Adoption, and Twin Research

Dace S. Svikis and Roy W. Pickens

INTRODUCTION

A number of methodological issues must be considered when family,

adoption, or twin methods are employed as research designs. Some

of these issues are common to all three research strategies, while

others are specific to each strategy. Failure to address these

issues appropriately during study design may adversely affect the

usefulness of the data obtained. It will do so either by clouding

interpretation of the findings or by severely limiting their usefulness and generalizability.

This chapter will briefly discuss several of these methodological

issues. The chapter is not intended as an in-depth or comprehensive discussion of these issues--the reader is referred to specific

chapters in the volume or to more advanced textbooks in behavior

genetics for that purpose (Fuller and Simmel 1983; Plomin et al.

1980). Instead, this chapter is intended to provide a background

for the reader who may be unfamiliar with the methodological issues

and assumptions involved in family, adoption, and twin research.

It is hoped that it will also provide a basis for better understanding the other papers included in this volume.

COMMON ISSUES

Methodological issues common to all three study methods include:

(1) appropriateness of diagnostic criteria; (2) differences in

methods of data collection; (3) distinction between prevalence and

incidence; (4) controlling for effects of age of risk; (5) sex

differences in data analysis; (5) influence of experimenter bias;

(7) influence of recruitment bias; (8) influence of assortative

mating on interpretation of results; (9) comorbidity in substance

abuse; (10) problems caused by abstainers in determining genetic

effects; and (11) across-drug generality in interpretation of

results. Some of these issues will be discussed in greater detail

under each specific method considered.

120
Diagnosis

Criteria used to identify a disorder are of fundamental importance

to clinical research and should be specified operationally. Unless

such criteria are known, the generalizability of the findings

cannot be determined. Differences in definitions are thought to

account in part for discrepant findings across studies. For example, twin, family, and adoption studies of alcoholism have variously defined the disorder by membership in Alcoholics Anonymous,

admission to an alcoholism treatment center, arrest for public

drunkenness, an inability to control drinking, or meeting DSM-III

criteria for Alcohol Abuse/Dependence. Other studies have failed

to provide any diagnostic criteria.

Data Collection

Archival records, questionnaires, and personal interviews are three

data sources typically employed in twin, family, and adoption

research. Each method has certain biases, however, and results may

vary as a function of the method selected. While archival records

are largely unaffected by experimenter bias, these data are retrospective, are often recorded in an unsystematic manner, and may not

provide sufficient detail for making psychiatric diagnoses. Questionnaires are simple to score and administer, and provide greater

structure and control over item content than archival records.

However, specific items may be poorly worded and ambiguous, causing

subjects to misinterpret them and provide inaccurate information.

Personal interviews allow investigators to follow up on subject

answers, which is not possible with questionnaires or archival

records. When interviews are unstructured, data are subject to

some of the same biases inherent in archival records (i.e., nonuniform data recording). With structured interviews, clarification

of responses is accomplished using probes, which are specific

queries concerning answers to questions. Although more time consuming, expensive, and difficult to administer than questionnaires,

the structured interview offers the most accurate and comprehensive

approach for obtaining information from subjects. Regardless

of the data collection method, reliability and validity

(corroborative) data should be obtained.

Prevalence vs. Incidence

Prevalence is the number of individuals exhibiting a disorder at

any particular point in time. Lifetime prevalence determines

whether the individual has ever had the disorder. Incidence, on

the other hand, refers to the rate of occurrence of a disorder

during a given period of time, usually one year. Thus, incidence

is the number of newly discovered or diagnosed cases of a disorder

(Burton and Smith 1970). For disorders such as drug abuse that are

characterized by intermittent periods of drug use and abstinence,

incidence and prevalence data may yield different estimates of the

frequency of actual drug problems. For most studies of biological

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vulnerability to drug abuse, lifetime prevalence is the most

appropriate statistic to use.

Age of Risk

The age at which symptoms first appear is another issue to be

addressed in twin, family, or adoption studies. If an individual

has not passed through the age of risk for a disorder, he/she

should not be labelled "unaffected," because a number of these

individuals may eventually develop the disorder. While age of risk

is frequently acknowledged, many studies fail to control for its

effects. This is particularly true in family studies of alcohol or

drug abuse, where children are often below the age of risk for

alcohol or drug abuse. Corrections should always be made for age

of risk of younger probands and other family members (Anderson

1982).

Sex Differences

Males and females show different rates of alcohol and drug problems, different ages of onset, and possibly different symptomatology as well. Therefore, caution should be exercised in

generalizing data from males to females. Data collected from males

and females should be analyzed separately, as important findings

may be obscured by merging of the data. Such analyses, however,

will require a larger number of subjects to achieve statistical

significance.

Experimenter Bias

Persons collecting data may inadvertently influence responses of

subjects through subtle verbal or nonverbal cues. If that person

has a vested interest in the outcome of a study, this may result in

a more favorable outcome. Experimenter bias, however, will not

affect all subjects uniformly. Rather, certain subjects (i.e.,

those with a high need for approval) may be more susceptible to

experimenter bias than other subjects. To the extent possible, all

interviewers, research assistants, etc., should be kept blind to

placement of subjects in experimental or control groups, family

history, zygosity, etc.

Recruitment Bias

Another potential source of bias is the method employed to recruit

subjects. In psychological research, subjects are frequently

recruited on a volunteer basis. Volunteers, however, differ from

nonvolunteers on many variables including intelligence, education,

occupation, socioeconomic status, and need for social approval,

among others (Rosenthal and Rosnow 1975). These data suggest that

volunteers may not be representative of the general population, and

thus caution must be used in generalizing findings from volunteers

to the population at large. Also, it is important to obtain data

from as many subjects in the original sample as possible.

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Sample Characteristics

Prevalence is usually represented as an average for a given population. However, actual prevalence will not be uniformly distributed

throughout that population. Rather, prevalence may vary as a

function of age, sex, marital status, educational background, rural

vs. urban setting, ethnic background, and socioeconomic status.

Thus, caution should be exercised in generalizing findings from a

nonstratified sample to the entire population, as data collected

from a subsample may not generalize to the entire population, and

vice versa.

Assortative Mating

Statistical formulae employed to calculate relative contributions

of genetic and environmental factors in a disorder often assume

that mating is panmictic. That is, choosing a mate is a random

process with respect to the characteristic being studied. However,

this assumption is often violated by assortative mating (i.e., the

selection of a spouse with similar characteristics). There is

substantial evidence for assortative mating among humans (Buss

1985). Several studies suggest that assortative mating plays a

role in the familial clustering of alcoholism (Stabenau and

Hesselbrock 1983). The influence of assortative mating should

always be considered in interpretations of study results. Suggestions for controlling for the effects of assortative mating will be

discussed below under each research strategy.

Comorbidity

In addition to drug abuse, many individuals show evidence of

alcoholism, depression, and/or antisocial personality disorder

(Meyer 1986). When more than one disorder exists in an individual,

it is important to determine their interrelationship. For example,

did alcohol abuse lead to symptoms of depression, or did depression

lead to the development of alcoholism? Investigators typically

distinguish multiple disorders on the basis of chronology. Thus,

if sociopathic symptoms (e.g., stealing, fighting) predate alcohol

abuse (e.g., heavy drinking, blackouts), then the diagnosis is

primary sociopathy with secondary alcohol abuse. If, however,

symptoms of alcohol abuse occurred prior to sociopathy, then the

individual is diagnosed as a primary alcohol abuser with secondary

sociopathy. It is important to distinguish between primary and

secondary disorders, as evidence for a genetic factor in one disorder may, in fact, represent a genetic predisposition for the

other disorder. Because multiple diagnoses are common in alcoholism and drug abuse, a thorough psychiatric evaluation should be

performed on all subjects in genetic research.

Problem With Abstainers

For both alcoholism and drug abuse, a specific environmental factor

must be present for the disorder to manifest itself. This factor

is exposure to alcohol or drugs. Individuals who are lifetime

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abstainers will never develop the disorder. When analyzing twin,

family, or adoption data, it is therefore important to examine the

drug and drinking histories of all nonproblematic individuals. It

is an open question as to whether data from nonproblematic individuals who never used alcohol or drugs should be included in

analyses. Exclusion of abstainers may enhance the magnitude of the

familial/genetic effects that are found.

Across-Drug Generalities

At present it is unknown whether findings obtained with one type of

drug abuse (e.g., heroin addiction) can be generalized to other

types of drug abuse (e.g., cocaine abuse). Such findings may or

may not generalize across drugs, or may generalize only within drug

classes (e.g., opiate abuse, stimulant abuse). Whenever possible,

studies should focus on specific drugs, or specific classes of

drugs. However, it is recognized that this may be impractical in

twin and adoption studies, where problems in finding a sufficient

number of subjects may exist.

FAMILY STUDIES

Methodological issues in family studies include: (1) selection of

any appropriate control group; (2) differences in methods of data

collection; (3) accuracy of information supplied by family members;

(4) procedures for handling unknown drug-use status of relatives;

(5) importance of collecting data from both first-and second-degree

relatives; and (6) influence of assortative mating on familial

patterns of inheritance.

Control Group

A familial pattern is evident if a disorder occurs more frequently

in relatives of probands than in relatives of controls. Selection

of controls is important, as abnormally high control rates will

obscure a familial effect while abnormally low control rates will

falsely suggest such an effect. Ideally, control groups should be

matched with probands for relevant demographic (and at times clinical) characteristics. It is an open question as to what constitutes an appropriate control group for family studies of substance

abuse. In various studies, control groups have ranged from hospital employees to psychiatric inpatients (Cotton 1979). It is

inappropriate to use population base rates of substance abuse as a

control if proband families deviate significantly from the general

population. To serve as a proper control in such cases, population

base rates must be adjusted for sex, age, and socioeconomic status.

Methods of Data Collection

Two methods for collecting familial data are the family history and

the family study. The family history method collects data about

family substance use from a single individual, the proband. The

family study method involves separately collecting data from each

family member. While the family history method is economical, it

124
typically provides an underestimate of prevalence of disorders

among family members, and its accuracy varies with types of disorders and relationship of family member to proband (Thompson et

al. 1982). While more accurate, the family study method is expensive, particularly when large families are involved. A compromise

approach involves interviewing the proband and one other family

member (Schuckit 1981).

Accuracy of Information Supplied

To corroborate information supplied by the proband about his/her

own substance use, spouses and children have been found to provide

more accurate information than parents or siblings (Mendlewicz et

al. 1975). When information about family members is obtained from

more than one source, informants may disagree about status of a

given family member. Several methods for resolving this dilemma

have been proposed, including (1) use of most frequent diagnosis

(i.e., consensus), (2) randomly selecting data from informants, and

(3) use of most severe status reported. Since family history data

have low sensitivity, that is, the modal diagnosis is not affected,

the third approach may be most accurate and is thus often preferred

by investigators.

Unknown Status of Relatives

Probands are sometimes unable to provide substance-use data about

all family members. In such cases, responses of "no" should be

clearly distinguished from "don't know," and every effort should be

made to obtain the missing data. At times, when data on a family

member were unknown, the status of the relative has been coded

negative (i.e., not present), leading to an underestimation of

familial influences In substance abuse. A more appropriate

classification of such cases would be "unknown" or “data not

present."

Data From Second-Degree Relatives

In many family studies, data collection is limited to first-degree

relatives (parents, siblings, and children). For adult-onset

disorders, data collection is often limited to parents and siblings

because children may not have passed through the age of risk.

While they are not genetically or environmentally as close to the

proband as first-degree relatives, collecting data on seconddegree relatives (grandparents, aunts/uncles, nieces/nephews, and

grandchildren) allows the data base to be broadened. This is

especially important for probands with no siblings.

Assortative Mating

Since substance abusers may mate assortatively with other substance

abusers, it is important to collect information on substance use by

the spouse, as well as by the spouse's other family members (Hall

et al. 1983). Since assortative mating can also occur for other

factors that may be related to substance use, such information

125
should be collected from proband and spouse as

ethnic background, socioeconomic status, other

orders, etc.

well, including

psychiatric disADOPTION STUDIES

Methodological issues in adoption research include: (1) representativeness of biological and adoptive parents to the general population; (2) influence of selective placement of adoptees on adoptive

parent-child correlations; (3) informant bias; (4) influence of

prenatal factors on biological parent-child correlations; and

(5) effects of time spent with biological parents on biological

parent-child correlations.

Representativeness of the Sample

Critics of adoption studies have contended that biological parents

adoptees are not representative of parents in the general population. Therefore, heritability estimates based upon this sample

may not be representative of all parents. Some studies have

suggested that the biological parents of adoptees do not differ

significantly from the general population in terms of personality

or other characteristics (Scarr 1977, cited in Plomin et al. 1980).

However, other studies have found excess rates of personality

disorders in unwed mothers who give up their babies for adoption

compared to unwed mothers who decide to keep their babies (Horn

and Turner 1976). Apart from characteristics of the biological

parents, the representativeness of adoptive or rearing parents must

also be examined. Adoptive parents tend to be better educated, in

higher socioeconomic groups, and less affected by psychiatric

problems than biological parents of adoptees (Fuller and Thompson

1978). Caution must therefore be exercised in generalizing results

from adoptees to the general population. In addition, control

groups should consist of adoptees, rather than members of the

general population.

Selective Placement

The rationale of the adoption method assumes that adoptees are

randomly placed in adoptive homes. However, selective placement

occurs when agencies attempt to match children to adoptive parents

who share characteristics in common with the biological parents.

When it occurs, selective placement confounds interpretation of

adoption study results. If selective placement occurs for a

genetically determined trait, the adoptive parent-child correlation

will be increased, which will reduce the estimate of the obtained

genetic effect. In contrast, if selective placement occurs for a

trait that is environmentally determined, the biological parentchild correlation will be increased, thereby increasing the

estimate of the obtained genetic effect. In adoption studies,

attempts should be made to determine the degree of similarity

between adoptive and biological parents for the characteristics

being examined, in order that appropriate statistical adjustments

can be made during data analysis.

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Informant Bias

When the biological mother is the sole source of information about

the adoptee, she may be unwilling or unable to specify paternity of

the adoptee. Studies have shown that paternity is incorrectly

reported in 5 to 10 percent of adoption cases (Murray et al. 1983).

Also, biological mothers may deliberately or unknowingly provide

inaccurate information about the biological father's occupation,

education, income, etc. To the extent possible, attempts should be

made to obtain corroborating information from the biological father

or other family members.

Influence of Prenatal Environment

In theory, the adoption study method attempts to separate nature

from nurture by establishing conditions where biological parents

supply the genetic component and adoptive parents supply the

environmental component to an individual's development. In

reality, biological parents also contribute early environmental

influences (from conception to birth and from birth to adoption).

Prenatal factors are especially important in adoption studies of

alcoholism and drug abuse when maternal alcoholism or drug abuse

may be present. Exposure of the developing fetus to alcohol or

other drugs during pregnancy may place the children at higher risk

for alcoholism or drug abuse. This would result in spuriously high

correlations between traits shown by the biological mother and the

child, which would not be genetic in origin. These risks can be

minimized by limiting studies to children of male alcoholics or

drug abusers or by examining children with either the male or the

female parent affected (or both). While this reduces the generalizability of the results, it does not entirely eliminate such

influences as the tendency of male alcoholics to mate assortatively

with heavily drinking females (Stabenau and Hesselbrock 1983).

Information on patterns of alcohol and drug use by both biological

parents needs to be obtained.

Influence of Early Rearing Environment

In addition to prenatal environment, adoptees also share at least

part of their early rearing environment with the biological parents. The more time a child spends with the biological parents,

possibly the greater will be the environmental influences provided

by those parents. In an adoption study of alcoholism, Cloninger et

al. (1981) found that adoptees of biological alcoholic parents who

resided with their biological mother for at least 6 months were 1.5

times more likely to develop later alcohol abuse than were those

adopted at an earlier age. However, other variables may also contribute to these results. Information on time spent with biological parents should be routinely collected in adoption studies.

Assortative Mating

The adoption method assumes that biological parents of adoptees

mate randomly. However, studies have shown that biological parents

127
of adoptees mate assortatively for a number of physical and behavioral characteristics (Plomin et al. 1977). Among biological

parents, assortative mating for alcohol drinking has been shown

(Rimmer and Winokur 1972; Hall et al. 1983), which increases the

genetic loading provided by the biological parents. Thus, the

pattern of alcohol and drug use by both biological parents should

be obtained, and investigators may wish to analyze their data by

number of alcohol or drug-abusing biological parents, a method

frequently employed in family studies.

TWIN STUDIES

When the twin method is employed to examine the role of genetic and

environmental factors in the etiology of a disorder, a number of

issues must be considered. These include: (1) whether twins are

representative of the general population; (2) whether twins who

participate in research projects are representative of twins in

general; (3) validity of equal environmental similarity assumption

underlying twin research; (4) accuracy of zygosity determination;

(5) importance of obtaining adequate sample of twins; (6) methods

of calculating concordance rates and heritability; (7) influence of

assortative mating on interpretation of results; and (8) importance

of obtaining population base rates in interpretation of results.

Representativeness of Twins

In the United States, the twinning rate is approximately 1 in every

83 live births. About one-third of twin births produce monozygotic

(MZ) twins; half the remaining two-thirds are same-sex and half are

opposite-sex dizygotic (DZ) twins. DZ twins tend to "run" in certain families, suggesting that hereditary factors may play a role

in their twinning. In contrast, MZ twins occur randomly in the

population (Plomin et al. 1980). Several studies have compared

twins to singletons on a variety of characteristics, including

cognitive abilities, personality factors, etc. While certain differences have been reported, they do not appear to influence the

generalizability of the results significantly (Fuller and Thompson

1978). Nevertheless, possible differences between singletons and

twins raise questions about the generalizability of twin findings,

and such generalizations should be made with caution.

Recruitment Bias

Volunteer bias has been reported in twin research. Among samesex adult twin pairs in the general population, approximately 50

percent are MZ and 50 percent are DZ, and 50 percent are male and

50 percent are female. However, volunteer subjects in twin studies

are typically two-thirds MZ and two-thirds female (Lykken et al.

1978). Thus, between-pair variance for DZ twins may be restricted,

resulting in an overestimate of the influence of genetic factors.

Similarly, data collected from a sample of male twins should be

less generalizable than data obtained from a sample of female

twins. To minimize recruitment bias, efforts should be made to

recruit all subjects in a sample, and to obtain data from both

128
members of as many twin pairs as possible. Incentives are often

used to encourage subject recruitment and participation by both

members of a twin pair.

Equal Environmental Similarity Assumption

An assumption underlying the twin method is that HZ and DZ twins

share equally similar trait-relevant environments. Therefore, any

observed differences in MZ and DZ twins must be due to number of

common genes. Research suggests that the in utero environment is

more similar for MZ than DZ twins in terms of positioning of ova

within the uterus, conditions necessary for egg implantation, level

of shared blood circulation, etc. (Lytton et al. 1977). However,

other in utero differences (e.g., distribution of cytoplasm to

cells) favor greater environmental similarity for DZ than MZ twins

(Schuckit 1981). These early environmental differences may influence later correlations between MZ and DZ twin pairs, and may be

mistaken for evidence of genetic differences.

Evidence exists that MZ twins also share more similar postnatal

environments than DZ twins. They are more often mistaken for one

another by parents, peers, and strangers; share more friends in

common; spend more time together; and show more similar preferences

in clothing, foods, etc. When degree of observed environmental

similarity was determined for MZ and DZ twins, higher correlations

were found for MZ than DZ twins. However, when environmental

similarity was correlated with similarities in cognitive and personality traits, only low correlations (ranging from -.06 to +.06)

for MZ twins were obtained (Loehlin and Nichols 1976). Thus,

increased environmental similarity did not result in increased

behavioral similarity, supporting the validity of the equal environmental similarity assumption. Other investigators have reported

similar findings (Matheny et al. 1976; Plomin et al. 1976). While

additional research is needed in this area, concern over this issue

should not significantly hamper future twin research.

Zygosity Determination

Accurate zygosity assessment (i.e., determining if twins are MZ or

DZ) is essential to the twin method. Misclassification of MZ and

DZ twins will result in higher correlations for DZ twins and lower

correlations for MZ twins for a genetically determined trait.

Several methods have been employed to determine zygosity. Of

these, blood-group analysis is the most accurate (and expensive),

with Lykken (1978) reporting 99.8 percent accuracy for 8 blood

types and 10 serum proteins and red blood cell enzymes. Unfortunately, the accuracy of self-report of zygosity is only 60 to 70

percent (Carter-Saltzman and Scarr 1977; Nichols and Bilbro 1966).

In studies of substance abuse, zygosity determination based on

similarity of physical appearance should be made with caution, as

discordant members of MZ pairs may get misclassified as DZ due to

differences in physical appearance caused by excessive alcohol or

drug use.

129
An inexpensive yet highly accurate method for determining zygosity

is use of questionnaire items such as "As children, were you and

your twin as alike as two peas in a pod?" and "Did even family

members have trouble telling you apart?" This approach has been

found to be 90 to 96 percent accurate in distinguishing MZ and DZ

pairs (Cederlof et al. 1961; Cohen et al. 1973). We have obtained

95 percent accuracy in use of the approach to classify alcoholic

twins (results confirmed by blood-group analysis).

Adequate Sample Size

Twins are rare compared to singletons, and twins with specific

disorders (e.g., alcoholism, drug abuse) are even more rare.

Further, some twins will refuse to be recruited, or have cotwins

who cannot be located. Thus, it is sometimes necessary to screen

large numbers of individuals to obtain an adequate sample size for

a study. Power calculations are used to determine the number of

twin pairs needed to distinguish between various MZ/DZ concordance

rate differences.

Concordance and Heritability

If a trait is dichotomous (i.e., either present or absent), concordance rates are computed. For pairwise concordance, number of

concordant pairs is divided by total number of pairs. Probandwise

concordance is computed similarly, except if both members of a pair

are ascertained in a sample they are counted twice (Gottesman and

Shields 1972). Concordance rates range from .OO (none of the pairs

were concordant) to 1.00 (all of the pairs were concordant). While

there are advantages to both methods, probandwise concordance is

usually preferred from a sampling perspective (Plomin et al. 1980).

A comparison of MZ and DZ concordance rates will provide an estimate of the role of genetic factors in the etiology of a disorder.

For continuous traits, heritability is calculated by Falconer's or

Holzinger's formula (Plomin et al. 1980), but Falconer's (1960)

formula is thought to give a more accurate estimate of heritability

(h2). As a population statistic, heritability possesses no absolute value and varies as a function of the specific environmental

factors operating upon a selected sample (Vernon 1979). Heritability estimates may also vary as a function of the population base

rates for a particular disorder. (For a more comprehensive review

of this topic, see Gottesman [this volume]). Numerically, heritability estimates range from 0.00 (solely environmental) to 1.00

(solely genetic). Assortative mating can confound interpretation

of heritability and must be adjusted for in the calculation.

For a discrete trait (i.e., drug abuse, alcoholism), concordance

rates may be used to provide a measure of heritability. The

formula for estimating heritability for a discrete phenotype is

(CMZ - CDZ)/(100 - CDZ), where CMZ is the probandwise concordance

rate for MZ twins and CDZ is is the probandwise concordance rate for

DZ twins (Allen et al. 1967; Smith 1974).

130
Assortative Mating

Assortative mating by parents of twins is an important issue in

twin studies of alcoholism or drug abuse, because it violates an

assumption on which heritability calculations are based. Assortative mating affects heritability estimates by increasing the additive genetic variance shared by DZ twins, but produces no change in

that for MZ twins (Plomin et al. 1980). For DZ twins, this increase in additive genetic variance will result in higher phenotypic correlations (i.e., DZ twins will appear more similar),

thereby reducing the magnitude of MZ and DZ differences. If twins

have parents who are heavy alcohol/drug users, it is important to

control for the effects of assortative mating in calculations of

heritability.

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studies. In: Galanter, M., ed. Recent Development in

Alcoholism. Vol. 1. New York: Gardner Press, 1983.

pp. 25-48.

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Plomin, R.; Willerman, L.; and Loehlin, J.C. Resemblance in

appearance and the equal environments assumption in twin studies

of personality traits. Behav Genet 6:43-52, 1976.

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unwed biological parents of adopted children. Science 196:449-

450, 1977.

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A Primer. San Francisco: W.H. Freeman and Company, 1980.

Rimmer, J., and Winokur, G. The spouses of alcoholics: An example

of assortative mating. Dis Nerv Syst 33:509-511, 1972.

Rosenthal, R., and Rosnow, R.L. The Volunteer Subject. New York:

Wylie-Interscience, 1975.

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In: Gedda, L.; Nance, W.E.; and Parisi, P., eds. Twin Research

3: Epidemiological and Clinical Studies. New York: Alan R.

Liss, Inc., 1981. pp. 61-70.

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J Hum Genet 26:454-466, 1974.

Stabenau, J.R., and Hesselbrock, V.M. Family pedigree of alcoholic

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ACKNOWLEDGMENTS

Matt McGue, Ph.D., of the University of Minnesota reviewed the

manuscript and provided helpful comments.

132
AUTHORS

Dace S. Svikis, B.A.

Clinical Services Manager, Alcoholism

Treatment Services D-5-C

Francis Scott Key Medical Center

4940 Eastern Avenue

Baltimore, MD 21224

Roy W. Pickens, Ph.D.

Director, Division of Clinical Research

National Institute on Drug Abuse

Parklawn Building, Room 10A5600 Fishers Lane

Rockvllle, MD 20857

133
Analytical Approaches to Twin and

Family Data

Matt McGue

INTRODUCTION

Theories of genetic and environmental transmission provide a basis

for predictions about the nature, magnitude, and pattern of familial resemblance. The relevance of these theories and their associated predictions extends beyond the mere demonstration that

genetic and/or environmental factors play a role in the etiology

of a given disorder. They also provide a framework for both identifying relevant research questions and developing efficient

research designs and analytical methods.

The supposition that a disorder may "run in families" implies the

need for a systematic approach to resolving the basis of this

familiality. Initially, it must be determined whether there is

familial resemblance for disease status. Next, is familial resemblance the result of genetic factors and/or common environmental

circumstances, and what are the magnitudes of their effects?

Finally, what are the nature and characteristics of the genetic

and environmental factors that contribute to disease etiology?

For genetic factors, this might involve resolving the mode of

inheritance and, if evidence of a major gene effect is found,

linkage studies in order to associate the gene with a specific

chromosomal location. For environmental factors, this might involve an assessment of the relevant factors and a demonstration

that they do, in part, account for environmental similarity among

relatives.

In the area of substance abuse, virtually nothing is known about

the existence of familial resemblance let alone the relative importance and characteristics of genetic and environmental factors.

Consequently, speculation about the existence of genetic mutations

that result in specific forms of human drug abuse and discussions

about analytical methods (such as segregation and linkage analyses

aimed at their characterization) are premature. Rather, the focus

here will be on research designs and analytical methods that can

provide necessary and basic information about familial resemblance. Specifically, models of genetic and environmental

134
transmission will be briefly described, and the designs and methods used for establishing familial resemblance, resolving the

components of familial resemblance, and characterizing the nature

of genetic and environmental factors will be outlined.

MODELS OF TRANSMISSION

Phenotypic Specification

In general, both genetic and environmental factors are assumed to

influence the development of a phenotype (i.e., characteristic of

interest). It is convenient, when considering their effects upon

familial resemblance, to characterize the different types of genetic and environmental factors. Genetic factors include additive

genetic effects as well as intralocus (i.e., dominance) and interlocus (i.e.,

1960).

epistasis) nonadditive genetic effects (Falconer

Environmental factors include familial environmental factors (i.e., social class and diet that are shared among family

members) and nonfamilial environmental factors (i.e., accidental

occurrences and peer groups that are not shared by family members)

(Jinks and Fulker 1970).

A general model of phenotypic determination is given by the structural equation

P= hG + dD + iI + cC + eE + w(GE)

Genetic Environmental Interaction

Effects Effects Effect

where capital letters are used to denote variables, and lower case

letters denote the effect of that variable on the phenotype. In

the equation, P denotes the phenotype; G, additive genetic factors; D, genetic dominance factors; I, epistasis factors; C,

familial or cultural environmental factors; E, nonfamilial or residual environmental factors; and GE, the interaction of genetic

and environmental factors. Although models that incorporate, for

example, interaction terms (Lathrop et al. 1984) or epistasis

(Williams and Iyer 1981) have been applied in the analysis of

family data, the general model is usually too complex and the

available family data not sufficiently informative to allow simultaneous consideration of all possible factors (Heath et al. 1984).

In practice, then, one initially adopts a reduced or simpler form

of the general model with the hope that, even in the general case,

it will still provide an adequate approximation. This model can

and should be extended if the simpler model does not account for

the family data.

A basic linear model that has been widely applied in human and

behavioral genetic research (Rao et al. 1984; McGue et al. 1983)

135
is given by the structural equation

P = hG + CC + eE.

The reduced model is achieved by assuming that all genetic effects

are additive and that there are no genotype-by-environment interactions. By imposing (without loss in generality) the additional

constraint that all variables are standardized to unit variance

and (with some loss in generality) the assumption that all variables are independent, the variance of the phenotype can be expressed as

1.0 = h2 + c2 + e2

which gives a partition of the phenotypic variance into proportions due to genetic (h2), familial environmental

familial environmental (e2) factors.

(c2), and nonThe model assumes that these three factors contribute to differences among individuals. Two of the factors (genetic and familial

environmental) also contribute to familial resemblance. But, as

their contributions differ depending on the particular familial

relationship involved, their separate influences can be resolved

as described below. The third factor does not influence familial

resemblance and includes systematic but nonfamilial environmental

influences as well as the unreliability associated with the

assessment of the phenotype. Although the three factors are, in

general, unobserved, a goal of twin/family studies and genetic

analyses is to identify these factors with specific observable

entities.

Liability Threshold Model

The stuctural equation models given above provide specifications

for quantitative phenotypes only. Many of the phenotypes of

interest are, however, qualitative or categorical (e.g., substance

abuse. schizophrenia. breast cancer. etc.). Falconer (1965)

introduced the notion of a threshold character and provided a unified framework for theories about the transmission of both quantitative and qualitative phenotypes. A threshold character is

assumed to be an expression of an underlying continuously distributed quantitative character termed "liability." The character is

expressed whenever an individual's combined liability exceeds a

fixed threshold value along the liability distribution (figure 1).

Wright (1934), in a series of classic breeding experiments on

polydactyly in the guinea pig, provided strong empirical support

for the threshold concert by demonstratino that a discontinuous

character (in this case an extra toe) could be the result of the

operation of many genes (in this case eight). The threshold model

136
FIGURE 1. Liabitity threshold model

NOTE: Affected individuals have liabiIity values that exceed the threshold value

T. Relatives of an affected individual are expected, if the disorder is

familial, to have higher mean liability values and thus greater risk than

the generaI population.

has now been applied to the analysis of family data from a wide

range of human disorders including schizophrenia (Gottesman and

Shields 1967), diabetes (Falconer 1967), and cleft lip and cleft

palate (Fraser 1970).

The liability threshold model can be used to derive familial risks

as a function of the heritability of liability (Smith 1971) and

has been extended to allow for multiple graded expressions of a

single liability distribution (e.g., in the case of substance

abuse, the gradation of cigarette smoking to marijuana use to hard

drug abuse) (Reich et al. 1972). The threshold model can also be

used to resolve the heterogeneity and association between related

diagnostic categories (e.g., between substance abuse and antisocial personality) (Cloninger et al. 1978). The liability

137
threshold model explicitly assumes that the transmission of a

qualitative phenotype is due to the transmission of the underlying

quantitative liability. The goal of twin and family studies of

qualitative phenotypes is, then, to identify and characterize the

genetic and environmental factors that contribute to this

liability.

FAMILIAL RESEMBLANCE

For qualitative phenotypes, familial resemblance is established by

demonstrating that relatives of an affected individual are at increased risk for developing the disorder, compared to the general

population. There are two general research designs used to establish familial resemblance. The proband method involves first selecting a sample of affected individuals (i.e., the probands),

then studying the probands' relatives to determine whether the

risk to relatives exceeds a known population prevalence value or a

baseline risk estimated from a simultaneously studied control

group. The family method involves observing a representative sample of families to determine whether there is a nonrandom distribution of disease status within families. For relatively rare

disorders (prevalence less than 10 percent), the proband method

yields observations on substantially more affected individuals

than the family method and will thus provide a more sensitive test

of the existence of familial aggregation. As substance abuse is

relatively rare (Robins et al. 1984), the remaining presentation

will focus on the proband method.

Table 1 gives the expected risks to first-degree relatives as a

function of the population prevalence of the disease and the

heritability of underlying liability. To simplify, all familial

resemblance is assumed to be due to genetic factors. Two characteristics of the table are worth comment. First, for rare disorders, low levels of familial risk may be consistent with high

levels of genetic involvement. For example, a risk to firstdegree relatives of only 2.9 percent is consistent with a

heritability of liability of 80 percent if the disorder has a

population prevalence of .1 percent. Second, familial risks are

functions of both population prevalence and heritability of

liability. Statistics such as relative risk that are based on

familial risk figures are, consequently, ambiguous concerning the

strength of familial resemblance. For example, the risk for

developing a disorder among the first-degree relatives of affected

individuals relative to the risk among the first-degree relatives

of unaffected individuals is 7.06 if the prevalence of the disorder is .001 and the heritability of liability is .40, but only

4.31 if the disorder has a population prevalence of .10 and the

heritability of liability is 1.0. The ambiguity of familial risks

underscores the importance of describing the familial resemblance

for qualitative phenotypes in terms of the tetrachoric correlations among liability values. Calculation of the tetrachoric

138
TABLE 1. Expected risks to first-degree relatives of an affected

individual as a function of the population prevalence

and the heritability of liability

Population Risk

Heritability Correlation .001 .010 .050 .100 .500

.20 .10 .003 .019 .074 .133 .532

.40 .20 .007 .034 .105 .172 .564

.60 .30 015 .056 .143 .216 .597

.80 .40 .029 .087 .188 .267 .631

1.00 .50 .054 .129 .244 .324 .667

---- .60 .095 .188 .311 .390 .705

---- .80 .263 .378 .495 .562 .795

NOTE: Correlations greater than .50 for first-degree relatives are not consistent

with complete genetic determination but are included to provide examples of

what the MZ twin risk might be in certain cases.

correlations, which are of course constant for varying prevalence,

requires knowledge of the familial risk as well as the population

prevalence and can be obtained using standard numerical approximations (Kirk 1973) or published nomographs (Smith 1970).

For a proband study, table 2 gives the number of first-degree

relatives one must observe in order to assure a statistical power

of .95 for detecting a significant increase in familial risk relative to a known population prevalence. For rare disorders of

known prevalence and moderate heritability, a large number of

first-degree relatives must be observed to assure adequate statistical power. This number is greatly increased if the prevalence

must be estimated in a simultaneously studied control group (not

shown in the table but derived using sample size calculations for

comparing two independently estimated proportions). For example,

for a liability heritability of .40 and a prevalence of .001, in

order to assure a power of .95, 994 first-degree relatives would

need to be studied if the prevalence is known, while 2,391 firstdegree relatives and 2,391 controls would be required if the

population prevalance were unknown. For more common disorders

that are at least moderately heritable, the required sample sizes

are moderate when the prevalence is known but remain large for

unknown prevalence. For example, for a known population prevalence of .05 and a liability heritability of .80, only 53 firstdegree relatives are required to achieve a power of .95. To

achieve the same level of statistical power when the prevalence is

unknown, however, 114 first-degree relatives and 114 controls are

needed.

139
TABLE 2. Number of independent relatives who must be studied to

detect an increase in familial risk

Liability

Correlation .001

Population Risk

.010 .050 .100 .500

.10 5,039 1,862 1,082 1,017 2,638

.20 994 371 247 240 656

.30 324 139 101 102 283

.40 138 67 53 54 153

.50 64 37 31 32 92

.60 33 21 19 20 59

.80 9 7 8 9 26

NOTE: The table shows the number of independent relatives who must be studied to

detect. with a statistical power of .95, an increase in familial risk over

a known population prevalence, using a one-tailed test at p=.05.

RESOLVING THE SOURCES OF FAMILIAL RESEMBLANCE

The basic linear model for the specification of a phenotype can be

extended to the phenotypes of several family members. If the subscript "i" is used to denote the individual, then

Pi = hGi + cCi + eEi.

The correlation between the phenotypes of any two relatives

(denoted by the subscripts "i" and "j") can be expressed as:

cor(Pi,Pj) = h

2

cor(Gi,Gj) + c

2

cor(Ci,Cj)

where cor(Gi,Gj) and cor(Ci,Cj) are, respectively, the correlations between the genotypes and familial environments of the two

relatives. Precise specification of these two correlations will

depend on the assumed model of phenotypic transmission.

Figure 2 provides a schematic representation or path diagram of

one model of phenotypic transmission that has been widely applied

in human and behavioral genetic research (Rao et al. 1979; McGue

et al. 1983). The path diagram depicts transmission within a

nuclear family consisting of a father, mother, and two children.

Using the basic rules of path analysis (Li 1975), one can derive

model-based correlations as functions of the four parameters of

140
FIGURE 2. Path diagram for the transmission of a quantitative

phenotype in nuclear families

NOTE: G, C, and P denote genotype, familial environment. and phenotype, respesctlvely. Subscripts F, M, 1, and 2 denote father, mother, and two children,

respectively. Parameters of the model are genetic heritability (h2

), cultural heritability (c2

), effect of parental familial environment on offspring’s familial environment (f), and correlation between the familial

environments of spouses (u).

the model: the genetic heritability (h2), the cultural heritability (c2), the effect of parental familial environment on offspring's familial.environment (f), and the correlation between the

familial environments of spouses (u).

Table 3 gives the model correlations for various familial relationships for both the general four-parameter case and the case

where environmental transmission mimics genetic transmission;

f=1/2 and u=O (i.e., the pseudopolygenic model) (Rice et al.

1978). The model correlations under the pseudopolygenic model

clearly illustrate that, if both genetic and environmental factors

141
TABLE 3. Model familial correlations

*Reared by common parents.

NOTE: The model familial correlations were derived as functions of the model and

the four parameters given in figure 2.

contribute to familial resemblance, the study of intact and typical familial relationships (e.g., parent-offspring, cousins, etc.)

will not resolve the two sources of familial aggregation (i.e.,

the weighting of h2 and c2 is the same within each relationship).

To examine the genetic and environmental contributions to familial

aggregation, three general approaches can be employed. First,

twin studies and their derivatives (e.g., twin families (McGue et

al. 1984)), as well as half-sibling studies, resolve genetic and

environmental influences by comparing the magnitude of phenotypic

resemblance between two relatives where the degree of genetic but

not environmental similarity varies (e.g., monozygotic (MZ) vs.

dizygotic (DZ) twins or full- vs. half-siblings). Second, adoption studies (Cloninger et al. 1984) allow direct estimation of

the importance of genetic and environmental factors through the

assessment of phenotypic similarity among biological relatives who

share no environmental factors and among adoptive relatives who

share no genetic background with the proband. Finally, the study

of intact nuclear families allows resolution of genetic and environmental influences if a measure of the familial environment is

available (Rao et al. 1984). For most behavioral traits, however,

the presumed complexity of the familial environment precludes

general application of this third approach.

The number of relatives one must observe in order to achieve a

given level of power for the detection of the influence of genetic

factors will, of course, vary depending on the design used (Moll

142
and Sing 1979; Heath et al. 1985). In the present paper, only the

two most basic designs--adoption and twin studies--will be considered. In an adoption study, establishing the significance of genetic factors is equivalent to demonstrating familial resemblance

among biological relatives who were reared apart. Therefore,

table 2 can be used to determine the number of first-degree relatives one must observe in order to achieve a statistical power of

.95. In a twin study, genetic factors are implicated if the MZ

concordance rate is greater than the DZ concordance rate. Assuming equal numbers of MZ and DZ twin pairs, table 4 gives the number of twin pairs of each type that would be needed to assure a

statistical power of .95 for the detection of genetic influences.

Note that, even for moderate levels of heritability, a sufficiently large twin sample will provide powerful tests for the existence

of genetic factors.

TABLE 4. Number of MZ and DZ twin pairs needed to detect

significant genetic effects

Model

h

2

 c2

.001

Population Risk

.010 .050 .100 .500

.40 .00 788 436 391 409 1,158

.40 .20 287 249 266 313 875

.60 .00 174 131 132 149 439

.60 .20 64 64 78 92 258

.80 .00 47 43 49 58 162

.80 .10 25 26 32 38 107

NOTE: The table shows the number of MZ and DZ twin pairs which must be studied In

order to achieve a statistical power of .95 for detecting significant

genetic effects, using a one-tailed test at p=.05.

It is worth while to compare the relative efficiency of twin and

adoption studies for detecting the influence of genetic factors.

If the population prevalence is unknown, then, relative to a twin

study, an adoption study requires fewer observations for low values of the heritability and an approximately equal number of

observations at higher values to achieve the same level of statistical power.

prevalence of .01 (h2=.40 and c

2 =.00), a twin study requires 872

For example, for a character with a population

relatives (i.e.,

only 371.

2 times 436), while an adoption study requires

For the same prevalence, when h2=.80 and c2=.00, the

twin study requires 86 relatives and the adoption study, 67.

Factors such as variable age of onset and unknown population prevalence will reduce the efficiency of the adoption study relative

to the twin study,

lation prevalence is

An example is the above case, where the popu-

.01 (h2=.40 and c2=.OO). If the population

prevalence must be estimated, however, an adoption study would

143
need to observe 804 first-degree relatives and 804 controls in

order to achieve the same level of power as 371 first-degree relatives with known prevalence and 872 twins with either known or

unknown prevalence.

Quantification of the magnitude of genetic and environmental

influences can be accomplished through analysis of the estimated

familial (tetrachoric) correlations (Rao et al. 1981; Rice et al.

1981). To illustrate, for schizophrenia the MZ and DZ twin concordance rates are, respectively, 44.3 percent and 12.1 percent

(Gottesman and Shields 1982). In the absence of additional information, all that can be concluded from these figures is that

genetic factors play a role in the etiology of schizophrenia.

Knowing that the population prevalence for schizophrenia is .85

percent (Slater and Cowie 1971) permits calculation of the MZ and

DZ twin liability correlations as .853 and .501, respectively.

These correlations can be further analyzed to yield estimates of

the parameters of the model. From table 3, the model-based twin

correlations are

rMZ = h2 + 2f2(1 + u)c2

and

rDZ = 1/2h2 + 2f2(1 + U)c2.

An estimate of genetic heritability is then given by

h

2

 = 2(rMZ - rDZ) = .704.

Observations on additional familial relationships are required to

identify the remaining parameters of the model and to test the

goodness-of-fit of the model to the family data. General likelihood methods have been developed to estimate parameters and test

hypotheses from categorical family data (Rao et al. 1981; Rice et

al. 1981). However, these methods require, in addition to family

data, information on the population prevalence of the disorder.

CHARACTERIZATION OF GENETIC AND ENVIRONNENTAL FACTORS

The goal of any twin/family study is ultimately to identify those

genetic and environmental factors that contribute to disease etiology. For genetic factors, this would involve resolution of the

mode of inheritance and, if evidence of a major gene effect is

found, linkage studies and analyses in order to associate the gene

with a specific chromosomal location, For environmental factors,

this would involve an assessment of the relevant environmental

factors and determination that the factors contribute to disease

liability.

144
Behavioral pheontypes do not usuallly show simple Mendelian

patterns of inheritance (e.g., recessive, dominant, etc.). For

non-Mendelian categorical characters, genetic methods such as

segregation and linkage analyses appear to have only limited power

(Risch and Baron 1984). In order to resolve complex patterns of

inheritance and genetic heterogeneity for such qualitative characters, it may be necessary to identify and use as alternative

phenotypes the quantitative factors that contribute to disease

liability.

The relationship between a quantitative risk factor and the expression of the disease can be characterized by observing both the

risk factor and disease status of each individual. The basic linear model can be extended to allow for two or more observations

(i.e., phenotypes) as

Pi = hiGi + ciCi + eiEi

where the subscript now denotes phenotype. The correlation

between phenotypes "i" and "j" is given by

cor(Pi,Pj) = hihjcor(Gi,Gj) + cicjcor(Ci,Cj) + eiejcor(Gi,Gj).

The correlation between two characters is thus partitioned into

genetic, familial environmental, and nonfamilial environmental

components. Multivariate genetic methods seek to resolve the

components of phenotypic covariation through analysis of multivariate family data (DeFries and Fulker 1986). A quantitative

risk factor with a high environmental but low genetic correlation

with the disease status phenotype should provide insights concerning probable environmental mechanisms in disease etiology, while a

quantitative risk factor with the reverse pattern of correlation

should suggest possible genetic mechanisms.

The relationship between immunoglobulin E (IgE) and the inheritance of allergies illustrates the utility of multivariate genetic

analyses. Briefly, allergies affect a sizeable proportion of the

population, are familial, and genetic factors appear to play a

major role in their etiology (Marsh et al. 1981). It has been

hypothesized that the inheritance of allergies is mediated by the

inheritance of IgE (Willcox and Marsh 1978). Indfviduals who

inherit high levels of IgE possess a generalized hypersensitivity

for developing allergic responses which may be expressed in several ways depending on early exposure.

The hypothesized relationship between IgE and the inheritance of

allergies can be tested by analyzing family data where both allergies and IgE levels have been assessed in all individuals. As

part of the Tucson Epidemiologic Study of Obstructive Lung Disease, Lebowitz et al. (1975) assessed IgE levels and responses to

145
skin prick tests for five different aeroallergens in 332 Caucasian

nuclear families (1,313 total individuals). The within-person

(biserial) correlation between positive response on the skin prick

test and log IgE is .403 for adults and .471 for children (both

significant at p<.05). Table 5 gives the familial correlations

for positive skin prick response, log IgE, and between positive

skin prick and log IgE. Note that there are substantial and significant between-phenotype familial correlations. If the inheritance of IgE accounts for the transmission of allergies, then the

between-phenotype familial correlation should equal the square

root of the product of the two within-phenotype familial correlations. The correlations in table 5 are generally consistent with

this expectation. For example, for mother-offspring, the square

root of the product of the two within-phenotype correlations is

.234, a value that does not differ markedly from the betweenphenotype correlation of .206. These data suggest, then, that the

genetic transmission of allergies may be due to the transmission

of IgE, which can now be the focus of future attempts to understand the genetics of allergies. Indeed, recent studies have

shown that a recessive gene that influences IgE levels also contributes to risk for developing allergies and may explain the

familial aggregation of allergies (Borecki et al. 1985).

TABLE 5. Familial relationahip between allergies and IgE in the

Tucson Epidemiologic Study of Obstructive Lung Disease

Familial Correlations

Relationship

Positive Between Skin Prick

Skin Prick Log (IgE) and Log (IgE)

Father-Offspring .147 .146

Mother-Offspring .243 .226

Siblings .250 .266

Father-Mother .076 .055

.162*

.206*

.167

.082

*Average of parent skin prick minus offspring log (IgE) and offspring skin

prick minus parent log (IgE).

CONCLUSION

Substance abuse is a relatively rare disorder. Epidemiologic

Catchment Area estimate of the lifetime rate for drug abuse/

dependence is slightly greater than 5 percent (Robins et al.

1984). Little is known about its familial aggregation. This

presentation focused on the types of twin/family designs needed to

determine whether substance abuse is familial and, if so, the

characteristics of the factors that contribute to familial risk.

Several conclusions are warranted.

146
Family studies allow one to determine whether there is familial

aggregation for the disorder, but not whether that aggregation is

due to genetic and/or familial environmental factors. The power

of a family study for identifying familial aggregation depends on

whether the population prevalence of the disorder is known. If

the prevalence is unknown, a much larger study is required to

achieve the same level of statistical power than if it is known.

Twin and adoption studies allow one to resolve the genetic and/or

environmental sources of familial aggregation. If the prevalence

is known, an adoption study will provide a more powerful test for

the existence of genetic factors than a comparably sized twin

study. The reverse is true, however, if the prevalence is unknown. From a practical perspective, at least in the United

States, twin studies may be easier to execute than adoption

studies. The twinning rate of approximately 1.2 percent insures

that there will be a sufficiently large population of substanceabusing twins to make a large twin study feasible. Twin and

adoption studies should be undertaken in the drug abuse area.

Concordance rates in the absence of prevalence data are not fully

informative concerning the basis of familial resemblance. Availability of prevalence data allows one to: (1) fit and test the

adequacy of various models of phenotypic transmission and (2)

quantify the magnitudes of genetic and environmental influences

through estimation of statistics such as the genetic heritability. The power of genetic analysis is greatly enhanced by population prevalance information.

Characterizing the genetic and environmental factors that contribute to disease etiology will require twin/family designs where

disease status as well as quantitative genetic and environmental

risk factors are assessed for all participants. Multivariate

designs and analyses will be needed.

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1934.

AUTHOR

Matt McGue, Ph.D.

Department of Psychology

University of Minnesota

Elliott Hall

75 East River Road

Minneapolis, MN 55455

149
Exploring Drug Abuse With Genetic

Strategies: Cautionary Tales

Irving I. Gottesman

INTRODUCTION

Sir Francis Galton could hardly have imagined that his suggestion

in 1875 that the relative powers of Nature and Nurture could be

uncovered by the study of twins would have led to the proliferation

of twin studies in the 20th century. During the last quarter of

the 19th century, Galton had noted the occasional appearance of

twins with similar forms of insanity as well as a greater similarity in intellect and personality in same-sex twins than in

opposite-sex twins. Great advances have been made from these crude

beginnings, but it was not until 1930 that Luxenburger, a German

psychiatrist, put twin research on a firm scientific footing with

the requirement that sampling of the twin types be systematic and

unbiased. He could easily show that case reports from the psychiatric literature were overloaded with identical twins and that most

of them were concordant for whatever disorder was reported. Data

gathered in such a fashion could not reveal the truths about the

contribution of genetic and environmental factors to the etiology

of psychiatric disorders. Nowadays, we recognize that familiality

of psychopathology can arise from the sharing of genes and/or

environments. Most often, some combination of genetic and environmental factors does the best job in accounting for the observed

facts, even when the problem, disorder, or disease has a primary

cause known to be nongenetic.

For the past half century of research on twins with mental disorders, the results have usually been reported in the form of

concordance rates for identical and fraternal twins, with separate

rates for the two sexes. Our thesis is that such concordance rates

leave much of the meaning unextracted from the twin data. Furthermore, alternative hypotheses and additional perspectives about

social, ecological, and biological (but not genetic) contributors

to the likelihood of developing psychiatric disorders can be generated by twin data and by contrasting twin data with those from

family and adoption strategies.

150
Our intent is not to criticize the literature in this area, but

rather to show how additional meaning may be extracted from the

data reported, once probandwise concordance rates (Allen et al.

1967) have been transformed into tetrachoric correlation coefficients and evaluated within the framework of multifactorialthreshold-polygenic (MFTP) models (Falconer 1965; Falconer 1967;

Gottesman and Shields 1967; Reich et al. 1972; Reich et al. 1975a).

Such a model has been found useful in the analysis of such diseases

as diabetes, schizophrenia, alcoholism, coronary heart disease, and

tuberculosis. These conditions are familial, common in the general

population, i.e., not rare like the mendelizing diseases, and do

not lend themselves to easy explanations in terms of mendelian

genetics. We shall use the MFTP model to examine twin studies of

schizophrenia, affective disorders, alcoholism, criminality,

tuberculosis, and dyslexia in a search for models that may be most

useful for adaptation to drug abuse and dependence. Alternative

models are not excluded by our analyses, but they are not considered further in this paper.

Nothing said here should be construed as antagonistic to the idiographic (Allport 1937), descriptive psychiatric (Jaspers 1963;

Slater and Roth 1969) approach to twin studies. Careful case

histories and descriptions are of paramount importance to understanding the etiology of psychopathology. A number of twin

researchers have provided detailed case histories supplementing

their summary statistics and permitting an appreciation of the

nuances and subtleties of psychopathology that cannot be gathered

in any other way (Essen-Moller 1941; Kringlen 1967; Rosenthal 1963;

Slater and Shields 1953; Tienari 1963). In our view, twin studies

are a means to an end and not an end in themselves. Additional

observations from spouses, adoptees, siblings, parents, and offspring are required to reduce the ambiguities inherent in the

study of twins "in a vacuum."

PRELIMINARY PRECAUTIONS

Certain precautions are required before the twin method can even be

suggested for the study of various types of psychopathology. After

all, twins are studied to enable researchers to generalize to the

general population of nontwin patients exhibiting those pathologies

studied. If twins are not representative of the general population

of patients, or if twinship per se correlates with certain kinds of

psychopathology, the method will generate results that cannot be

generalized. Unlike many other research strategies, the adequacy

of the twin sample can be verified by internal checks on the proportion of the two sexes, the proportion of various zygosities,

and whether twins are overrepresented in the reference population

of schizophrenics, criminals, or drug addicts. Racial factors are

important in these determinations as well (Bulmer 1970).

After infancy, about 2 out of every 100 Caucasian individuals in

the United States and Western Europe are twins. This fact should

encourage government-supported researchers to begin twin registers

in their own settings; it also provides a benchmark against which

151
to evaluate the possible excess of twins with any particular diagnosis. Among individuals with mental deficiency, about 4 percent

are twins, twice the expected rate. Twins comprise 6.7 percent of

cerebral palsy cases (Hanson 1960).

Some common complications of pregnancy are even more common among

twins and may have an effect on studies of psychopathology with

differential effects by race. Relevant information can be found in

Price (1950), Bulmer (1970), and Parisi (1974). Given the explicit

and implicit sources of central nervous system (CNS) damage to

twins, together with confounding factors such as organic mental

disorders, mental retardation, and pervasive developmental disorders, it would be difficult to conduct a twin study of early

infantile autism (EIA) and have results generalizable to the general population of autistic children. It is uncertain, but likely,

that twins occur in excess in populations of autistic children

(Hanson and Gottesman 1982). Using computerized tomography (CT)

scans, Campbell et al. (1982) showed that 11 of 45 young autistic

children had significantly enlarged ventricles. Folstein and

Rutter (1977) reported that 11 pairs of EIA monozygotic (MZ) twins

contained 4 concordant pairs, all probands, for a probandwise rate

of 53 percent; none of 10 dizygotic (DZ) pairs were concordant; 13

of 25 EIA twins experienced significant biological hazards ranging

from delay in delivery of the second-born to neonatal convulsions.

The point is that traits or disorders confounded by obstetrical

complications associated with twinship should be analyzed cautiously (Reveley et al. 1981).

One fact established about twinning that is relevant to some

aspects of psychopathology is the relationship between maternal age

and DZ twinning. MZ twinning is not associated with maternal age

and appears to be a relative constant at 3 to 4 deliveries per

1,000. DZ twinning, however, is dependent on maternal age, parity,

and race (Bulmer 1970; Parisi and Caperna 1981). At age 20, 3 per

1,000 deliveries among Caucasians are DZ twins; in the midthirties,

15 per 1,000 deliveries are DZ twins. The net effect of this

phenomenon is to insure that maternal age in a random sample of

fraternal twins will be higher than in a random sample of identical

twins. For disorders in which maternal age at time of birth is

considered relevant to psychopathology, for example, antisocial

personality (Aichorn 1935) and its legal consequences, and possibly

drug abuse and alcoholism, we might expect a difference in the

prevalence of such behaviors in samples of fraternal compared to

identical twins (Cloninger et al. 1978). Older, more mature

mothers may be better disciplinarians for their sons than younger

mothers (Johnson 1959). A diminished prevalence of criminality,

delinquency, or drug abuse, if observed in fraternal twins, is the

phenomenon to be explained, not something peculiar about identical

twins, such as "identification," which leads to an excess of

pathology in identical twins.

152
THRESHOLD DISEASES, PSYCHIATRIC DIAGNOSES, AND CORRELATIONS IN

LIABILITY

The seminal paper by Falconer (1965) on the inheritance of liability to certain diseases, estimated from the "incidence" among

relatives, permitted-the joining of the methods for quantitative

genetics, with its long history in agriculture and biometrics, to

the clinical genetic observations about apparently qualitative

differences between the relatives of normals and the relatives of

affected probands, i.e., starting index cases. The methods require

the assumption that the disorder, such as dependence on substance

X, has an underlying, continuous, normally dfstributed liability

that is, conceptually, the final common pathway for all relevant

genetic and environmental contributors. The qualitative information about the proportion of proband relatives similarly affected

is transformed into a correlation in the underlying liability by

means of the tetrachoric correlation coefficient or its equivalents. Bivariate normality is also assumed. The prevalence or the

lifetime risk in the general population specifies the threshold

point. Some biases inherent in the methods of Falconer were

modified by Edwards (1969), Smith (1970), and Smith (1974).

If one were to make the unsafe assumption of no trait-relevant

environmental similarities between relatives,the correlation in

liability derived from Smith (1970), equals Rh2 (R = the coefficient of genetic relationship; 1.0 for identical twins, and 0.5 for

fraternal twins and other first-degree relatives in the absence of

assortative mating) multiplied by h

2 (heritability of liability).

Thus, it follows that the heritability for any set of relatives is

equal to the phenotypic correlation coefficient divided by the

genetic coefficient of relationship, but only after a number of

simplifying assumptions. The graphical solution to r will contain

some error, especially when the population risk exceeds about 5 or

6 percent, as it will for many forms of drug and alcohol abuse. We

also caution that heritability estimates have very large standard

errors with the usual twin sample sizes (Martin et al. 1978), so

that we offer these techniques in the context of discovery and

hypothesis generation. The heritability derived from these procedures is narrow sense heritability, which refers only to the

proportion of total variance associated with additive genetic

factors. Broad sense heritability, on the other hand, includes

variance associated with dominance, assortative mating, and epistasis (i.e., gene x gene interaction) (Falconer 1981). If we set

the variance in total liability equal to V, it can be decomposed

into all genetic variance, VG, + VU + VC, where VU is the withinfamily environmental variance that makes siblings unique, and VC is

the between-family variance that siblings share in common and that

makes them alike. We use the notations VU and VC rather than E1

and E2 associated with the Jinks and Fulker (1970) and Eaves et al.

(1978) approaches to avoid the implication that an analysis of

variance has been conducted for the correlations derived from the

MFTP approach.

153
We shall extract some of these components of liability from twin

data below. First, we must make the important point that concordance rates disembodied from the associated population risk lead to

ambiguous conclusions in regard to the etiology of a disorder.

Table 1 selects two representative concordance rates for identical

twins: 50 percent and 80 percent. The body of the table shows

that the meaning attached to the concordance rate is completely

dependent on the associated population risk. Thus, a concordance

rate of 50 percent in identical twins can be an indication of

either a highly heritable trait (given a low population risk) or a

disorder with trivial genetic contributions as the population risk

increases, such as for marijuana use in young adult twins. Concordance rates in identical twins as high as 80 percent are

difficult to interpret in isolation, but they imply high correlations in liability even with very high population risks. As we

shall show shortly, however, very high correlations in liability

for identical twins may occur in the context of disorders with no

heritability. The quantity known as relative risk is calculated

from the risk in relatives divided by the population risk. We show

this quantity to make the point that it is not a useful indicator

to the kinds of problems we deal with in psychiatric genetics.

Although very high relative risks point toward something genetic,

low relative risks do not exclude high heritability.

TABLE 1. MZ correlations in liability to a multifactorial disorder

with fixed concordance rates*

*Correlation in liability from graphical solution in Smith (1970)

SOURCE: Derived from Gottesman and Carey 1983.

The correlations in liability for identical and fraternal twins

cannot be used as two independent estimators of heritability in the

broad sense, because they contain other variance components. Besides genetic variance, it is reasonable to suspect a priori. that,

for behavioral traits, nongenetic familial effects (VC) contribute

to the phenotype correlation. The equations below show the basic

twin correlations in terms of variances as well as the general

equations for total variance in liability and h2

B and h2N.

154

Population

Risk (%) At r=50% Relative Risk At r=80% Relative Risk

.1 .92 500.0 .99 800.0

1.0 .87 50.0 .98 80.0

5.0 .80 10.0 .96 16.0

10.0 .72 5.0 .95 8.0

20.0 .62 2.5 .95 4.0

50.0 .00 1.0 .80 1.6
With twin data, we only have two observations, the MZ and DZ correlations in liability, plus the constraint that the proportions

of variance components must sum to 1 (equation 1). From the equations there are six unknowns, but we can only estimate three of

them. For our purposes, we make the assumptions of no dominance

(VD) and no epistasis (VEp).

should not be too critical,since additive genetic variance is the

In general, this simplification

largest component (Morton 1982). We also assume no assortative

mating recognizing that its presence will result in an underestimation of genetic effects and an overestimation of common

environment. The need to make these assumptions demonstrates how

important it is to complement twin data with data from other types

of relationships, to reduce uncertainty. For substance abuse

(Reich et al. 1975b) as well as for affective disorders, known

values for assortative mating can be entered.

By taking two times the difference in correlation coefficients, we

obtain, via equation 4, an estimate of the magnitude of genetic

effects that will be an overestimate if dominance (VD) or epistasis

(VEp) variance is important, or an underestimate if assortative

mating is important. We can estimate the quantity VC via

equation 5, by subtracting the identical twin correlation coefficient from two times the fraternal twin coefficient. We can estimate the quantity VU, the unique environmental influences, by

subtracting the identical twin correlation from 1. Whenever the

fraternal twin correlation exceeds .5, it is a clue to the need to

search for VC and/or assortative mating. The assumptions one wants

to make abou the sources of genetic variance other than V t A in

equations 4 and 5 are critical for their application to twin data

for any particular psychiatric disorder or trait (Carey and Rice

1983).

Unlike table 1, which fixed concordance rates, table 2 fixes the

heritability as high (.8) or low (.2) and shows various combinations of identical and fraternal twin concordance rates that will

yield such high or low heritabilities. Once again, the general

population risk for the disorder similarly defined is critical. It

is clear that low absolute levels of concordance either for identicals or for fraternals is still compatible with high heritabilities

155
for disorders with the kinds of population risks observed for the

so-called functional psychoses. As the population risk for a

disorder increases toward 20 percent, as it will for alcohol and

drug abuse in some sectors of society, the moderate concordance

rates generated in twins do not yield evidence for appreciable

genetic contributions. In this table, the relative risks as well

as the ratio of the MZ:DZ concordance rates are given. Both

quantities are ambiguous indicators of facts better determined

directly from the correlations in liability. Notice that both high

and low relative risks are compatible with high heritability and

that considerable variability in the ratio of concordance rates

occurs, despite the fixing of the heritability at .8.

TABLE 2. Expected concordance rates for high (.8) and low (.2)

heritability disorders

High Heritability Low Heritability

Population M Z DZ Relative Ratio MZ

Risk (%) (%) (%)

DZ Relative Ratio

Risk* MZ%/DZ% (%) (%) Risk* MZ%/DZ%

.1 26 2.8 260/28 9.3 .65 .28 6.5/2.8 2.3

1.0 38 8.5 38/8.5 4.5 5.30 1.90 5.3/1.9 2.8

5.0 50 19.0 10/38 2.6 10.50 7.50 2.1/1.5 1.4

10.0 55 26.0 5.5/2.6 2.1 17.00 13.00 1.7/1.3 1.3

20.0 65 35.0 3.2/1.8 1.8 28.00 23.00 1.4/1.2 1.2

*Concordance/population risk, MZ/DZ.

SOURCE: Derived from Gottesman and Carey 1983.

THE LIABILITIES TO PSYCHIATRIC DISORDERS AND ALCOHOL

DEPENDENCE/ABUSE

As noted earlier, one of the biggest deterrents to interpretation

of twin concordance rates for different psychiatric disorders is

the absence of risks in the general population for disorders

similarly defined and diagnosed. Twin data were selected where

population risks are presented or easily determined to reevaluate

twin data in the literature. Table 3 presents a reanalysis of the

classical twin study on alcoholism conducted by Kaij (1960) in

Sweden. Kaij's findings included census data on the general population of Swedish males indicating various levels of alcohol

abuse. Only information from official records is presented and

used, although Kaij analyzed the data based on his personal

followup of most of the twins. Although the total sample consisted

of 59 MZ probands and 146 DZ probands, some of the definitions lead

to small sample sizes. For example, only seven MZ probands were

chronic alcoholics. Again, our analysis is meant to be exploratory. All definitions for alcohol abuse in terms of severity

result in substantial heritabilities, although it does appear that

156
chronic alcoholism may be more heritable than the others. One fact

that emerges from this analysis is the trivial contribution to the

liability to chronic alcoholism from common familial effects, VC,

which would include such factors as social class and family attitudes toward drinking. As the definition for alcohol abuse is

broadened in the cotwins, such common environmental factors take on

considerable weight. One clue to this phenomenon is the correlation in liability for fraternal twins exceeding .50. One analysis

was derived from selecting as probands those twins who were defined

only at level b, that is, having a single conviction for alcohol

abuse during their careers. By using any definition of alcohol

abuse in cotwins, we found a 36 percent concordance rate for both

MZ and DZ pairs. The resulting correlations in liability were both

.60, which guarantees a zero heritability. In this kind of analysis, for what may be called mild alcohol abuse, it appears that all

the variance in liability is nongenetic, with VC equal to .60 and

VU equal to .40. Our cautions above, about the assumptions required before using the equations, should be stressed. Many other

lessons relevant to the drug abuse field can be gleaned with the

information in table 3.

In table 4, we present reanalyses using the methods above for some

conditions to stimulate drug abuse researchers interested in

genetic possibilities. The data on affective disorders are taken

from the important twin study by Bertelsen (1979) and Bertelsen et

al. (1977) conducted with the Danish Twin Register. His total

sample consisted of 110 pairs. We use his best guess as to the

population risk for manic-depressive psychosis (bipolar + unipolar), 1.2 percent, and then estimate the population risk for

bipolar psychosis as a proportion of that total risk using data

given by Bertelsen. The credibility of our reanalyses for the data

in table 4 would be undermined by using population risks gathered

in different countries by clinicians with differing orientations

toward diagnosis. By restricting ourselves in this fashion, we

believe we can make more sense of the data. Our expectation that

bipolar psychosis would be more heritable than manic-depressive

psychosis as a whole could not be confirmed. The bipolar probands

are nested within the manic-depressive probands; the remaining

cases are unipolar. Although both categories of affective psychoses are highly heritable, there is considerable room left for

common family variance, VC.

The data tables for schizophrenia come from a pooling of the modern

studies on schizophrenia in twins (Gottesman et al. 1982). All

concordance rates are probandwise (Allen et al. 1967). The criteria for diagnosing cotwins can be equated with the population

risks for definite (.85 percent) and for definite plus probable

(1.17 percent) reported by Slater and Cowie (1971) for Western

European psychiatric epidemiology, coinciding with the location of

the twin studies. Schizophrenia appears to be as heritable as the

affective psychoses despite the lower concordance rates for identical and fraternal twins. Unlike the affective psychoses, the liability to schizophrenia appears to be little influenced by common

family variance. However, the total nongenetic variance is .30,

157
TABLE 3. Severity thresholds for alcoholism and the consequences

for concordances and heritabilities in Kaij’s Swedish

twin study

Defini- Defini- Probandwise

tion tion Popula- Concordance

for for tion

Proband Cotwin Risk (%) MZ% DZ% r M Z r D Z h

2

VC/V

(1) (2) (3) (3) (4) (5)

e e .57 86 10.0 .99 .50 .98 .01

cd+e e .57 24 7.5 .71 .44 .54 .17

b+cd+e e .57 15 4.1 .59 .30 .58 .01

e cd+e 1.90 100 30.0 1.00 .70 .60 .40

cd+e cd+e 1.90 53 26.0 .87 .65 .44 .43

b+cd+e cd+e 1.90 46 23.0 .82 .60 .44 .38

e b+cd+e 7.70 100 30.0 1.00 .50 1.00 .00

cd+e b+cd+e 7.70 79 41.0 .97 .68 .58 .39

b+cd+e b+cd+e 7.70 61 39.0 .85 .64 .42 .43

(1) Definitions of severity from Kaij (1960): e = chronic alcoholism for 10 years,

cd = multiple convictions for intoxication, b = single conviction.

(2) Actual population prevalences reported by Kaij (1960) from a census of all

Swedish men in 1947--7.7 percent were noted to have alcohol abuse.

(3) Correlation in liability from graphical solution in Smith (1970).

(4) Broad sense heritability from equation 4.

(5) Variance in liability from shared environmental influences from equation 5.

SOURCE: Derived from Gottesman and Carey 1983.

the balance being made up of idiosyncratic or unique environmental

variance, or VU. With regard to schizophrenia, path analysis using

other degrees of familial relationship is convergent with the

analyses from twins (McGue et al. 1985; Rao et al. 1981).

The data on male and female criminality in twins represent a final

update on the initial sample for Christiansen's Danish twin study

(Cloninger and Gottesman 1987; Christiansen 1977). The probandwise

concordance rates shown in table 4 are not in need of age correction, as all the twins are through the risk period. The population

risks shown for felony offenses are the lifetime risks using the

total twin population from the Danish Twin Register for all twins

born in the eastern half of Denmark between 1881 and 1910, in which

both twins survived at least until age 15, the age of criminal

responsibility. The risks were calculated only from same-sex pairs

registered in the National Police Register and are very similar to

data for nontwins (Wolf 1965). The base population of twins from

which the offenders were identified consisted of 1,462 male pairs

158
TABLE 4. Twin data for disorders with population risks determined

by equivalent homotypic criteria

Popula- Relation tive

Risk Risk MZ:DZ

Disorder MZ% DZ% (%) MZ/DZ Ratio rM Z r D Z h

2

VC/V

Manic-Depressive

Psychosis 69 22 1.20 58/18 3.1 .95 .63 .64 .31

Bipolar Psychosis 79 19 .32 247/59 4.2 .99 .69 .60 .39

Schizophrenia (S) 44 12 .85 52/14 3.7 .85 .50 .70 .15

Schizophrenia

(S+?S) 46 14 1.17 39/12 3.3 .85 .50 .70 .15

Male Criminality

(Felony) 51 30 10.00 5/3 1.7 .74 .45 .58 .16

Female Criminality 33 13 1.60 21/8 2.5 .74 .45 .58 .16

REading Disability 91 45 14.00 6/3 2.0 .99 .61 .76 .23

Tuberculosis 87 26 1.37 64/19 3.3 .99 .66 .66 .33

and 1,580 female pairs. The male probands consisted of 73 MZ and

146 DZ twins, while the female probands consisted of 15 MZ and 28

DZ twins. The data on criminality provide a striking example of

how quite different concordance rates between the sexes still reduce to the very same correlations in liability and the consequent

heritabilities. For adult crime, as defined within this particular

sample over this particular time period (the twins were last followed up in 1977), we find marked heritability, a trivial contribution to liability from common family variance, but an appreciable

contribution from unique environmental factors (perhaps bad luck

and temptation). VU amounts to .26. Preliminary evaluation of

twins who are juvenile delinquents yields very different results:

no genetic variance and large VC estimates (Gottesman et al. 1983).

The results of these kinds of analyses are shown for two further

disorders: reading disability, with a population risk relevant to

drug use (14 percent); and tuberculosis, a known infectious, i.e.,

environmental, disease. The twin-based heritability for the

liability to tuberculosis is wrong; it is presented in order to

embarrass the method in this instance where we know that a bacillus

is the primary causal agent.

The information in table 5 from the risks to other relatives,

including spouses and half-siblings, can be fitted to path models

(McGue et al. 1985) to determine the heritability (h 2) and the

environmentability ("cultural transmissibility" or c2) of the

liability to this infectious disease. The results reveal that c2

is .62 and h2 is .06 for this classical data set (Kallmann and

Reisner 1943) on the relatives of cases. The twin-based value of

h

2

.66, is misleading and incorrect. The path model results reveal a role for genetic factors, albeit small at .06, in determining resistance to the bacterial/environmental vector. Could

159
such a model be relevant to understanding the role of genetic

factors in drug abuse/dependence?

TABLE 5. Rates of tuberculosis in relatives of tuberculosis index

cases, observed tetrachoric correlations, and expected

correlations under each of three path models

Tetrachoric Correlations

Model Expectations

Relationship Affected Environto Proband BZ* (%) Observed General mental Genetic

Spouses 197.5 7.1 .314 .281 .291 .00

Parents 676.0 16.9

25.5

.541 .558 .552 .50

Siblings 534.0 .663 .647 .649 .50

MZ Twins 55.0 87.3 .992 .992 .992 1.00

DZ Twins 164.0 25.6 .665 .647 .649 .50

Half-Siblings

(Reared by

Common

Parent) 33.5 11.9 .445 .611 .649 .25

*BZ = age-corrected sample sizes

NOTE: Family data were reported originally in Kallmann and Reisner (1943), age

corrections were made using the abridged Weinberg method, and tetrachoric

correlations were calculated using a lifetime risk for tuberculosis at that

time estimated by Kallmann and Reisner to be 1.37 percent.

SOURCE: Derived from McGue et al. 1985.

CONCLUSIONS

We have shown that the common practice of simply reporting probandwise concordance rates for psychiatric disorders leaves much of the

meaning unextracted from the data. We recommend that appropriate

population risks be determined and that the concordance rates be

converted into correlations in the liability toward developing the

disorder. Further manipulations of correlation coefficients result

in statistics that can be interpreted within the discipline of

quantitative genetics and may provide directions for further research. Many other innovations and developments have taken place

over the past decade of twin research and should be consulted by

those contemplating the use of twin strategies (Eaves et al. 1978;

Fulker 1978; Liston et al. 1981; Rose et al. 1980).

Twin strategies are alive and well but, like all strategies in

research, require an awareness of their limitations, assumptions,

160
and appropriateness. Our nation's current and future twin registers are an untapped gold mine for exploring the feasibility of

multifactorial genetic and environmental models for drug

abuse/addiction.

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ACKNOWLEDGMENTS

Preparation of this paper was aided in part by grants MH 31302,

AA 03539, and MH 36517 to Washington University School of Medicine

and a fellowship to the Center for Advanced Study in the Behavioral

Sciences, Stanford, CA, supported by the John D. and Catherine T.

MacArthur Foundation. This paper draws on earlier work (Gottesman

163
and Carey 1983; McGue et al. 1985), which presents some of these

ideas in greater detail.

AUTHOR

Irving I. Gottesman, Ph.D.

Department of Psychology

University of Virginia

Gilmer Hall

Charlottesville, VA 22903

164
Biological Vulnerability: Treatment

Implications/Applications

George E. Bigelow, Robert K. Brooner, Mary E. McCaul,

and Dace S. Svikis

INTRODUCTION

When this conference was being planned, we agreed to provide comments on the implications of biological vulnerability issues for

treatment of drug abuse. In some subsequent listings of the conference program, our topic, "implications," was changed to

"applications." This change led to some anxiety on our part, as we

felt that treatment application in this area would be premature at

this time. Clearly, though, utilization of biological vulnerability information to improve treatment efficacy and patient-treatment

matching is a desirable long-term goal. Thus, while we are perhaps

not yet able to proceed with valid therapeutic applications, certainly the developing data and issues in this area do have implications for how studies of biological vulnerability might proceed.

While this distinction between implications and applications may

seem like a trivial matter of semantics, we believe it is important; the words we select can carry with them unintended suggestions of what we believe to be the current developmental status of

our understanding of biological vulnerability issues.

To suggest that we can productively discuss treatment applications

of differences in biological vulnerability would be to imply that

we are fairly advanced in our understanding of this area. The

applications goal in studying biological vulnerability is that we

might ultimately be able to match appropriate treatments to individual characteristics. At present, however, we are far from such

a capability. To achieve this goal, we need to understand the

nature of and the differential processes inherent in individual

differences in biological vulnerability, as well as the elements

and processes of effective substance abuse treatment. Unfortunately, our knowledge in these critical areas remains in its infancy.

Thus, we offer at the outset our general conclusion that, at the

present time, our knowledge about the processes involved in biological vulnerability and effective drug abuse treatment are too rudimentary to allow us to use this information about individual

differences to guide differential treatment.

165
While we suggest that vulnerability differences and processes are

not yet developed or understood enough to have major application in

treatment delivery, we certainly believe that the data are strong

enough and the relationships important enough to have major implications for treatment. However, much more research is needed before it will be possible to translate these data and relationships

into practical therapeutic application.

The general organization of our discussion will be:

What is biological vulnerability?

How might it influence treatment?

How has it influenced treatment of disorders/diseases other than

drug abuse?

What is needed to achieve application in the drug abuse field?

INDIVIDUAL DIFFERENCES IN BIOLOGICAL VULNERABILITY

The concept of biological vulnerability refers to the entire range

of innate individual difference characteristics that might be associated with increased likelihood of an individual's developing a

drug dependence disorder. This innate biological vulnerability

should not be viewed as a dichotomous variable--with an individual

being either vulnerable or not--but rather as a multifaceted construct which varies along a continuum from high vulnerability to

low vulnerability. By definition, all drug abusers must have some

degree of biological vulnerability, otherwise they would be

biologically invulnerable and could not have become drug abusers.

The multifaceted nature of biological vulnerability is evidenced,

for example, in Oriental populations, which, despite the biological

protective factor of the flushing response to alcohol, continue to

display some degree of vulnerability to alcoholism. It is at

present unclear whether complete biological invulnerability exists.

It should be abundantly clear that there are great individual

differences in vulnerability to substance abuse disorders. Some

individuals become substance abusers, and others do not; some

become dependent, and others do not. The other presentations at

this conference indicate that a wide range of variables might serve

as markers of these individual differences in drug abuse vulnerability. Perhaps most prominent among these putative markers of

biological vulnerability is family history of substance abuse or

psychiatric disorder, but such markers might also exist in the

domains of personality characteristics, mood and affect, and neuropsychological or behavioral responses to drugs. A major scientific

challenge remains in determining the extent to which these various

markers of vulnerability represent biological (or genetic) as

opposed to acquired factors. Also, it remains unclear whether the

different markers all relate to the same vulnerability process or

whether there might be multiple, independent biological vulnerability processes operating.

166
POTENTIAL INFLUENCES

Regardless of how it is assessed and regardless of whether it is a

unitary or multifactorial construct, there are two general ways in

which an individual's biological vulnerability might influence

treatment decisions. These are in the areas of whether to treat

and how to treat. If knowledge of a patient's biological vulnerability status were to influence either one of these factors, this

would certainly represent an application of this knowledge to

substance abuse treatment.

Diagnosis

Diagnosis is the process of determining whether a specific disorder

is present. Thus, it is the critical step in deciding whether or

not to treat. Individuals with diagnosed disorders presumably

warrant treatment; intervention in the absence of a diagnosed disorder presumably falls into the domain of prevention rather than

treatment. If biological vulnerability information were to influence the diagnostic evaluation of individual patients, this would

clearly have a direct and major impact upon treatment decisions.

This is not used at present. Current DSM-III/IIIR diagnostic

criteria for substance abuse disorders do not include individual

vulnerability factors, e.g., family history of substance abuse, in

the process of diagnostic determination. If this were to be done,

it is possible that two patients with identical clinical presentations but with differing vulnerability characteristics might be

differently diagnosed and, consequently, differently treated.

The most likely context within which biological vulnerability

assessments might influence diagnostic decisions is that of the

patient with mixed symptoms, e.g., the case of the depressed

alcoholic with a positive family history for either depression or

alcoholism (but not both). In such a case, it is likely that the

patient's primary diagnosis would be that for which there was a

positive family history. Thus, although such diagnostic roles for

family history information do not appear in the official criteria

of the Diagnostic and Statistical Manual, practical clinical realities are likely to result in this type of diagnostic application.

Data concerning the validity of such applications are lacking at

present.

Treatment Methods

The clearest way in which biological vulnerability information

might affect treatment would be if different treatment modalities

or different treatment goals were prescribed for individuals with

differing biological vulnerability characteristics. This ability

to practice effective patient-treatment matching so as to maximize

therapeutic outcomes is perhaps the ideal applications goal for

studies of biological vulnerability. At present, data do not exist

to guide such differential treatment. However, as with diagnostic

applications, we need to recognize that practical clinical realities will likely result in treatment applications of biological

167
vulnerability information even in the absence of supporting data.

A likely application would be the prescription of more intensive or

intrusive treatments to patients with positive family histories, or

perhaps the prescription of those specific modalities to which the

patients' relatives responded.

Prognosis

A third way in which biological vulnerability factors might be

related to treatment deserves mention. This is as a possible

prognostic marker. For example, data from the alcoholism field

indicate that alcoholics with positive family histories, i.e.,

genetic loading, for alcoholism follow a more rapid and more severe

course of deterioration. A prognostic marker would not necessarily

have any influence at all upon the therapist's diagnostic and

treatment decisions. Thus, while it might be a correlate of treatment outcome, biological vulnerability status as a prognostic

marker might have no influence upon recommendations for patient

care. It is likely, however, that therapists would be more adamant

and aggressive in prescribing the usual therapies to individuals

whose prognostic markers indicate that they are at greater risk of

adverse outcome. This is a potential subtle influence upon treatment; the nature of recommended treatment is not altered, but the

therapist's motivation to deliver it might be.

OTHER DISORDERS

In order to obtain some framework or reference point with which to

discuss how biological vulnerability might influence drug abuse

treatment, it seems worthwhile to consider the examples of other

disorders or diseases for which biological predisposition has been

demonstrated. Perhaps examination of the historical examples

provided by these other disorders might tell us what applications

we could expect to see in the drug abuse treatment field. For this

exercise, we have chosen to consider the examples provided by a

selection of disorders for which a positive family history is known

to be a marker of increased biological vulnerability. Thus, we

discuss six different disorders with significant heritability:

three medical disorders and three psychiatric/behavioral disorders.

For the medical disorders, we have chosen to consider hypertension,

diabetes, and coronary heart disease (CHD). For each of these

three, a positive family history of disease is a significant risk

factor for an individual's developing the disease. The questions

we want to ask concerning these disorders are the following: Is

diagnosis of the disorder influenced by knowledge of the individual's family history? And, once an individual is diagnosed as

having the disorder, are any treatment decisions influenced by

whether or not the patient has a positive family history of the

disorder? For all three disorders, it appears that the answers are

"No." For none of these medical disorders does family history have

a significant impact upon either diagnosis or treatment decisions.

Rather, diagnosis is based upon objective aspects of the patient's

clinical presentation, and treatment decisions are based upon that

168
diagnosis and upon the clinical presentation of the individual

patient, regardless of the individual's family history of disease.

Thus, overall, the historical examples provided by these three

medical disorders suggest that biological vulnerability may have

little impact upon treatment. The diagnostic criteria for, and the

therapeutic response to, elevated blood pressure, elevated blood

glucose, or cardiac ischemia have been unaffected by family history

factors indicative of elevated biological vulnerability.

What about psychiatric/behavioral disorders? Is their diagnosis

and/or treatment affected by individual vulnerability considerations? As historical examples of the impact of biological vulnerability for psychiatric disorders, we have chosen to consider

schizophrenia, depression, and alcoholism. Again, as with the

medical disorders, we find no evidence that either the diagnostic

criteria for, or the therapist's response to, these disorders is

influenced by biological vulnerability/family history factors.

Rather, treatment decisions are based on the characteristics and

presentation of the individual patient, independent of family

history factors.

Thus, the historical examples provided by these six other disorders

tell us that we must be prepared for the possibility that biological vulnerability issues will similarly have little or no treatment

impact in the drug abuse area.

The primary area in which genetically loaded vulnerability factors

have affected the handling of medical disorders is that of prevention--primarily through the mechanism of early detection and

intervention. Thus, individuals with family histories of hypertension, diabetes, or CHD are typically advised to have periodic

diagnostic assessments to detect potential onset of disease as

early as possible. It may be the case that similar preventive or

early detection activities may be the chief domains in which biological vulnerability factors will influence our handling of

substance abuse disorders.

Also, though we are aware of no data on this issue, we suspect that

a close examination of the treatment of these other biologically

loaded diseases would reveal subtle influences upon therapist

behavior resulting from the prognostic implications of positive

family histories of the diseases. For example, a normal and

appropriate therapeutic recommendation for cases of ischemic heart

disease or adult-onset diabetes is a regular regimen of physical

exercise. We suspect that the likelihood and firmness with which

such an exercise prescription is made will be greater in patients

carrying the added risk factor of a positive family history. A

similar subtle effect on the therapist seems likely to occur in the

drug abuse treatment area.

169
PREREQUISITES FOR TREATMENT APPLICATION

The experience discussed above with other, non-drug-abuse disorders

suggests that biological vulnerability information may have little

if any impact on treatment. However, we think it is possible that

this information may come to have a very significant impact on drug

abuse treatment. Before such treatment applications can occur, it

will be necessary to have both scientific and practical advances in

several areas.

Recognition/Detection

Improved methods for identifying individuals with heightened vulnerability are needed. The emphasis in current efforts to identify

vulnerable individuals is upon family history. Yet it remains

unclear exactly what family history factors confer risk. Family

histories of drug abuse, alcoholism, antisocial personality, and

other psychiatric disorders are all among the candidates. We need

to determine which familial factors confer risk, and, if there are

multiple familial factors, we need to determine whether they all

confer risk of the same type or through the same mechanism. For

example, does a family history of one type of substance abuse/

dependence, e.g., alcoholism, confer increased risk for other

types, e.g., opiate abuse? Does a family history of multiple types

of disorder confer a different or greater risk than a family history of only one type of disorder? Once we know what the relevant

risk factors are, we need adequate methods for assessing those risk

factors. The methods used for assessment of vulnerability status

must possess adequate sensitivity and specificity; schemas with

high rates of false positives or false negatives will generally be

unacceptable for clinical application. Ideally, these methods

should yield a quantitative evaluation rather than a categorical

labelling of vulnerability status; quantitative evaluations permit

more precise differential assessments among individuals.

Unfortunately, the family history method has substantial weaknesses

on both of these last two points: it is imprecise, and it is categorical. In the family history method, patient vulnerability

status is categorized based upon the characteristics of the

patient's blood relatives. Since we do not yet know how to identify the vulnerability characteristic in an individual patient, we

look for markers in his/her relatives. However, there is substantial imprecision due to the facts that not all vulnerable individuals have positive family histories and not all individuals with

positive family histories display the vulnerability. Clearly, it

would be preferable if the vulnerability characteristic could be

directly detected and assessed within individual patients. Thus,

our major recommendation in this area is that efforts to identify

vulnerable individuals begin to focus upon characteristics of the

individual in coordination with characteristics of his/her family

members. These efforts will move us beyond the stage of using

family history as a rather global marker or risk factor and should

yield new information about the pathophysiological processes and

170
mechanisms involved in elevated substance abuse risk. This information will permit the design of treatment strategies specifically

targeted to those processes and mechanisms and is more likely to

yield acceptable levels of sensitivity and specificity of

detection.

At present, while we must continue to rely upon the family history

method for detection of biological vulnerability, improvements to

this methodology would be desirable. Different investigators use

different methods and it is not yet clear which methods for

assessing family history are most valid and appropriate. Some

investigators rely upon patient interviews, while others also

interview other family members. The severity of prior disorder

required for classification as family history positive varies

across studies. Evaluation and scientific consensus on techniques

for assessing family history would be useful.

Alternative Treatments

For differences in patient vulnerability characteristics to have an

effect on treatment, it is necessary that there be some variety

among treatment approaches. Assessing individual differences can

have little practical import if all patients are treated the same

regardless of that assessment. Alcoholism provides an example of a

field in which it is clearly documented that biological vulnerability plays a significant role but in which the available treatment

methods and goals are generally rather homogeneous--the major difference being whether treatment is delivered on a residential or an

outpatient basis. In the absence of significant treatment variety,

determination of the presence or absence of a positive family

history of alcoholism has no major impact on treatment delivery.

The situation with respect to treatment variety is only slightly

better in the drug abuse field, where the specific modality of

methadone maintenance is used with a significant number of

patients. If treatment is to be influenced by biological vulnerability assessments, it is necessary that a variety of treatments

be developed and that these treatments bear some meaningful relationship to specific, identified pathophysiological processes or

mechanisms associated with the heightened vulnerability.

Patient-Treatment Matching

The ultimate treatment applications goal for studies of biological

vulnerability is to be able to match patient subgroups to the specific treatment approaches that are most successful for individuals

with their identified characteristics. Therefore, once we are able

to identify the patient with a significant loading on biological

vulnerability, and we have alternative treatments to choose from,

the final step to achieving treatment application is to develop a

data base justifying such patient-treatment matching. This will

require a great deal of careful clinical research. Unfortunately,

at present most clinical therapeutics research in the substance

abuse field does not involve assessment of biological vulnerability

status or analysis of its relation to treatment response. The

171
studies that are needed must do more than examine the relation of

vulnerability status to treatment outcome. It is likely that

heightened vulnerability will be a correlate or predictor of poor

prognosis, but that simple correlation cannot justify differential

treatment decisions. What is needed are data indicating that the

relative efficacies of treatments A and B are reversed for patients

with and without high biological vulnerability, i.e., treatment A

is better for one group, while treatment B is better for the other.

If it should turn out that there are different types of biological

vulnerability operating through different mechanisms, then it would

be necessary to conduct similar research for each type.

CONCLUSION

At present, our understanding of biological vulnerability issues in

substance abuse remains in a primitive stage. Further understanding of the bases for individual differences in substance abuse

vulnerability offers considerable promise for improving the efficacy of substance abuse treatments. As our science advances, we

will understand better how to recognize or detect the individual

with heightened biological vulnerability, we will understand better

whether this biological vulnerability is a unitary or multifactorial construct, we will understand better the specific pathophysiological processes and mechanisms involved in expression of

this vulnerability, and we may understand better how to select

treatments that are specifically appropriate to the characteristics

of individual patients. The last of these steps--that of actual

application via patient-treatment matching--is the only one about

which we have significant uncertainty. While we feel certain that

our understanding will advance, we are less certain that this

improved understanding will yield treatment applications. Our consideration of other medical and psychiatric disorders with significant biological vulnerability loadings failed to reveal instances

of treatment application of vulnerability information for those

disorders. Applications in the prevention field seem certain to

accrue from studies of biological vulnerability; applications in

the treatment field remain a scientific challenge and a yet-to-befulfilled hope.

ACKNOWLEDGMENTS

Preparation was supported in part by U.S. Public Health Service

grants DA-00050 and AA-07026.

172
AUTHORS

George E. Bigelow, Ph.D.

Robert K. Brooner, Ph.D.

Mary E. McCaul, Ph.D.

Dace S. Svikis, B.A.

Behavioral Pharmacology Research Unit

D-5 West; Psychiatry Department

The Johns Hopkins University School of Medicine

Johns Hopkins/Key Medical Center

4940 Eastern Avenue

Baltimore, MD 21224

173
The Applications of Biological

Vulnerability Research to Drug Abuse

Prevention

Edward Kaufman

INTRODUCTION

Alcoholism studies are well ahead of drug abuse research in the

understanding of biological vulnerability to substance abuse and

dependence. The papers that are presented in this monograph attest

to the disparity of knowledge between the two fields. There are

several as yet unanswered questions about the relevance of existing

alcoholism findings for drug abuse. These questions include:

(1) How much of the conclusions based on alcoholism studies of

biological vulnerability are directly applicable to drug abuse?

(2) Which studies should or can be replicated? (3) In view of the

high prevalence of alcohol abuse among drug abusers and of drug

abuse in alcoholics, to what extent are the two groups made up of

the same persons? (4) How often is the family of procreation of

one generation's alcoholic the family of origin of the next

generation's drug abuser? (5) What can we learn from studies of

biological vulnerability to alcoholism, and from alcoholism

prevention efforts, that is applicable to the prevention of drug

abuse?

Several difficulties in comparability between alcohol and drug

abuse studies readily come to mind. Scotch, bourbon, or beer,

alcohol is the same drug. Valium is different from heroin and even

more different from cocaine. Amphetamines are neither PCP nor

amyl nitrite. Thus, with hundreds of drugs of abuse, we should

expect more heterogeneity in drug abusers and difficulties in

tracing patterns over generations, which shift from one drug to

another. Another clear difference is that alcohol is legal, and

most drugs of abuse are not. Thus, drug abusers are more likely to

commit illegal acts and therefore more likely to be diagnosed as

antisocial personalities (ASPS), validly or not.

Meisch and George (this volume) presented animal studies demonstrating that strains of rats that are selectively bred for high

alcohol intake are the same strains that show high morphine

intake. Also, Pickens and Svikis (this volume) found evidence to

suggest that the pattern of inheritance for drug abuse is similar

174
to that for alcoholism. This suggests a predisposition to drug

taking in general rather than to any one specific substance. It is

unknown, at present, if this phenomenon provides evidence for a

combined receptor site or a final common pathway of drug satiation,

craving, etc.

Animal research has shown that monkeys will continue to selfadminister cocaine (unlike any other drug) until death. This is

the only commonly used example of an animal study cited by teachers, therapists, and prevention specialists in an attempt to

dissuade vulnerable individuals from ever trying cocaine (Cohen

1981). It would be interesting to know if dissemination of knowledge such as this is helpful in preventing cocaine abuse. Perhaps

animal researchers should attempt to breed selectively for highand low-cocaine-seeking animals; such research might help prevent

cocaine abuse by providing knowledge about the genetics or neurobiology of cocaine-resistant individuals.

Stabenau (this volume) cited studies that show increasing risk for

alcoholism and antisocial personality (ASP) with increasing number

of alocholic parents. If neither parent is alcoholic, the risk for

alcoholism in progeny is 6.5 percent, and the risk for ASP is 2.8

percent. If one parent is alcoholic, the risks are 15 percent and

10 percent, respectively, and if both parents are alcoholic, the

risks are 36 percent and 31 percent, respectively. Cloninger et

al. (1986), in their Swedish adoption study, found 22.8 percent of

adopted-out sons of biological fathers registered for alcohol abuse

were themselves alcohol abusers, as were 28.1 percent of adoptedout sons of alcoholic biological mothers. If we trace alcoholic or

drug-abusing sons back to their fathers, we find a very high

prevalence of drug and alcohol abuse and dependence. These data

have potentially broad implications for prevention, which may or

may not be implementable. An alcoholic should be aware that the

risks of his or her child's becoming an alcoholic are four to five

times greater than those of the nonalcoholic. If two alcoholics

are married to each other, they should be aware that the odds of

bearing an alcoholic child are far greater. Although most children

are born before their parents' alcoholism becomes recognizable, the

onset of parental drug dependence generally occurs before children

are born. Thus, it is of considerable importance and possibly

greater utility to demonstrate the role of genetic transmission in

drug abuse so that drug abusers could be made aware of the possible

consequences, should they have children. The comunity at large

could be made aware of the vulnerability of these children, as

could the children themselves.

Rounsaville (this volume) emphasizes the present difficulty in

assessing the genetic transmissibility of opioid dependence because

the parents of today's opioid addicts were extremely unlikely to

have been exposed to opioids. In my own earlier work (Kaufman

1981) and that of Zeigler-Driscoll (1979), rates of parental alcoholism in opioid abusers were found to be 33 percent and 63 percent, respectively. In 1976, I treated one family of a heroin

addict where four of his five children were also heroin addicts.

175
Over the next decade, many children of the heroin addicts of the

1960s and early 1970s will be entering the age of drug vulnerability. Thus, this is an important time to perform studies of substance abuse disorders in the parents and children of opioid

addicts.

We know that many of the children of severe drug abusers are at

risk for substance abuse and psychiatric dysfunction. However, we

have not yet established the extent of the risk for drug abuse, as

we have for alcoholism. Not all children of alcoholics are dysfunctional; in fact, some appear to be highly functional. These

apparently overfunctioning children of alcoholics may do so at the

expense of gratifying their own needs, because they have become

accustomed to meeting everyone's needs except their own as a result

of growing up within an alcoholic family. The data on the various

roles of the children of alcoholics have not been well documented

by scientific studies. However, there is presently an opportunity

to perform state-of-the-art family system research on the roles of

children of adult drug abusers. We must also search for the mechanism that enables some children of substance abusers to function

overcompetently. Is their apparent health explained by genetic,

societal, or family system factors?

Another factor that needs to be researched in these families is

sibling birth order. In my own preliminary studies of heroin

addicts, the youngest sibling was often heroin addicted. There was

frequently a highly competent oldest sibling, who took over the

role of the early-departed father (Kaufman 1981). Addiction, in my

study, appeared to be related to the parents' need to have a

perennial child to care for in order to avoid focusing on their own

relationship. Studies of birth order and sibling roles need to be

further defined and quantitatively demonstrated.

Wegscheider's (1974) descriptions of different sibling patterns in

alcoholism should be quantitatively assessed to see if comparable

roles exist in children of drug abusers. Studies done by Black et

al. (1986) of the consequences of being the child of an alcoholic

also need to be replicated with children of drug abusers. If

definitive, problematic roles in children of drug abusers can be

clearly described, then the detrimental aspects of these roles can

be prevented through education of parents and children. There is

also a need to determine if certain childhood roles lead to specific adult psychopathology. For example, are youngest siblings

most vulnerable? Are oldest siblings spared? Does the "family

hero" become the overachieving adult? Does the family scapegoat

become the drug-dependent adult? Does the lost child become

schizoid or schizophrenic? Long-term, prospective followup studies

can give us the answers to these key questions in the prevention of

substance abuse and psychological disability in the progeny of

substance abusers.

Studies by Cadoret et al. (1985) suggest that male/female differences in alcoholism rates reflect socially determined greater

exposure to alcohol rather than different genetic transmission. In

176
part because of the low rate of female alcoholism, the genetics of

this group has not been well studied. Preliminary studies suggest

different etiologic factors for males and females (Pickens and

Svikis, this volume; Cloninger, this volume). However, with

women's increasing exposure to drugs and alcohol, we can expect

higher rates of female drug and alcohol abuse and dependence. With

female dependence on some drugs, e.g., benzodiazepines, higher than

male dependence, it is critical that the interaction of genetics

and environment be studied in the progeny of drug-dependent females. Over the past few years, we have begun to develop trait

markers for substance abuse risk (Tarter, this volume). These

include: (1) low platelet serotonin and low monoamine oxidase with

related sensation seeking; (2) decreased amplitude of the P300 wave

of the event-related potential; (3) increased truncal ataxia;

(4) decreased intensity of reaction to modest doses of ethanol;

(5) possibly diminished alpha-wave activity (slow waves) in EEGs,

with a greater possibility of alpha waves after drinking; and

(6) intense changes in cortisol and prolactin secretion in response

to an acute ethanol challenge. Another high-risk group are those

children with attention deficit disorder and early antisocial

behavior. These markers, if carefully shown to be replicable in

demonstrations of individual. vulnerability, could, if combined with

family pedigree data, help predict who is at high risk for alcohol

abuse and perhaps for drug abuse. Certainly investigation of these

phenomena in male children of male drug abusers is warranted, to

determine if the findings parallel those reported for alcoholism.

However, even if we identify a high percentage of children at risk

for drug abuse, we must consider to what extent our prevention efforts should target this group. If we do target high-risk groups,

it should never be at the expense of diminishing comprehensive

prevention efforts. Perhaps these studies of markers could be used

to discourage certain types of advertising that might appeal to

potential substance abusers, particularly those who have high

sensation-seeking traits. Substance abuse by individuals with

proclivities for sensation seeking might also be prevented by

encouraging drug-free sensation-seeking activities such as Outward

Bound. There is sufficient evidence that a general prevention

effort should be made to encourage children of alcoholics, drug

abusers, and ASPS to choose a path of total abstinence from drugs,

alcohol, and cigarettes. How to communicate this message

effectively is another potential area for research. It would be

helpful to know what proportion of the children of substancedependent individuals and ASPS can use substances moderately

without eventually becoming dependent. Can some of these children

be taught that the first time they use substances to intoxication

or in any other problematic way should be the last time they use or

use immoderately? How can we determine which of these children can

use drugs or alcohol without becoming addicts or alcoholics? Certainly children of substance abusers and ASPS who are in a pattern

of recurrent substance use should be informed of their high-risk

status and encouraged to work toward a lifetime of abstinence.

They must learn that they cannot drink, smoke, or take drugs like

other children. Another problem in targeting high-risk children is

177
the risk of stigmatizing them. Although our concern about

stigmatizing them should never be an excuse for doing nothing, we

must try to help these children without their becoming the subject

of damaging peer ridicule or critical teacher scrutiny.

One proposal would be to educate all school children about factors

associated with vulnerability and give them the opportunity to

volunteer for services that are provided in a discreet way. In

most communities, there are no support groups for children of drug

abusers that function in the way Alatot and Alateen do for children

of alcoholics. There is no movement at all in drug abuse comparable to the apparently effective Adult Children of Alcoholics

group. The National Institute on Drug Abuse should support the

development of these groups as well as evaluate their effectiveness. Chemical dependency groups are still continuing to

function; these could be used to seed Narcotot and Narcoteen.

Communities could be encouraged to begin an "Adult Children of Drug

Abusers" movement. The effectiveness of these groups with drug

abusers should be researched more thoroughly than they have been

with alcoholics. A child-of-a-drug-abuser questionnaire should be

developed, which can identify these children before they manifest

overt problems, so that problematic behavior can be prevented.

There is no single method of prevention that can, in isolation,

make a dent in the substance abuse problem. Prevention must be

comprehensive and deal with all aspects of the problem. We must

work with the three-generational system of the children of drug

abusers. Their parents need help in parenting skills and communication, whether they be intact families, single parents, blended

families, common-law relationships, or extended family networks.

The entire family system needs substantial assistance, whether the

drug abuser is still living with them, drops in occasionally, or

has abandoned them totally. This assistance should be provided

without stigmatizing these families. Thus, services must be

offered voluntarily and discreetly.

Perhaps the knowledge we have gained at this meeting and the

knowledge about alcoholics as it is replicated with drug abusers

can be utilized to target high-risk schools where the majority of

students are at risk. Another high-risk group are children in

juvenile facilities and group homes. Comprehensive attempts at

prevention could be universally implemented with these high-risk

children, and should include the following.

(1) Training of high-risk children should include how to "say no"

and the building of self-esteem.

(2) Counselling should be performed by an effective, well-trained,

student-respected, readily available staff counsellor. This

counsellor should come from within the educational system.

Staff can be supplemented by peer counsellors, who should be

well trained, given school credit for their training and

counselling time, and well supervised.

178
(3) Parents should also be involved in the effort, including the

use of educational groups, directive multiple family therapy,

and parenting and communication classes. Self-help groups for

children of all ages and for parents should be made available.

(4) Training should be provided for all teachers to help them

recognize substance abuse problems and deal with students who

present these problems.

This comprehensive approach to prevention in a high-vulnerability

school could be matched with a comparable "school as usual" and

would be an interesting research project, which could substantially

affect future prevention efforts. Separate aspects of school-based

prevention programs could also be evaluated individually. These

modalities could be compared across approaches or to a matched

"school as usual" having little or no prevention activity.

Recent studies on biological vulnerability in schizophrenia have

been very helpful in shifting the thrust of family therapy efforts

with this group to a more educative approach. The techniques that

have been developed to diminish hostility, criticism, and overinvolvement on the part of the families of schizophrenics have been

found to be very helpful (Goldstein et al. 1978; Anderson 1983).

These techniques developed only after the concept of biological

vulnerability to schizophrenia was accepted. The more we can demonstrate biological vulnerability in the progeny of drug abusers,

the more we can shift our family treatment approach to an educational model. My presentation certainly raises more questions

than it answers. However, the relative absence of studies on

biological vulnerability in the children of drug abusers and the

total absence of any work on the application of this concept to

prevention support the need for questioning our approach.

It is hoped that this technical review will raise many critical

questions in this rapidly emerging field that can be answered with

appropriate, relevant, scientific methodology.

REFERENCES

Anderson, C.M. A psychoeducational program for families of

patients with schizophrenia. In: McFarlane, W.R., ed. Family

Therapy in Schizophrenia. New York: Guilford Press, 1983. pp.

99-116

Black, C.; Bucky, S.F.; and Padilla, S.W. The interpersonal and

emotional consequences of being an adult child of an alcoholic.

Int J Addict 21(2):213-231, 1986.

Cadoret, R.J.; O'Gorman, T.U.; Troughton, E.; and Heywood, E.

Alcoholism and antisocial personality. Arch Gen Psychiatry

42:161-167, 1985.

Cloninger, C.R.; Bohman, M.; and Sigvardsson, S. Inheritance of

alcohol abuse: Cross-fostering analysis of adopted men. Arch

Gen Psychiatry 38:861-868, 1981.

Cohen, S. Gift of the sun or the third scourge of mankind? Drug

Abuse Alcohol Newslett 10(7):1-3, 1981.

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Goldstein, M.J.; Rodrick, E.H.; Evans, J.R. May, P.R.A.

Steinberg, M.R. Drug and family in the aftercare of a

; and

cute

schizophrenia. Arch Gen Psychiatry 35(1):69-77, 1978.

Kaufman, E. Family structures of narcotic addicts. Int J Addict

16(2):273-282, 1981.

Wegschieider, S. The Family Trap. Minneapolis: Johnson Institute,

1974.

Zeigler-Driscoll, G. The similarities in families of drug dependents and alcoholics. In: Kaufman, E., and Kaufmann, P., eds.

Family Therapy of Drug and Alcohol Abuse. New York: Gardner

Press, 1979. pp. 19-39.

AUTHOR

Edward Kaufman, M.D.

Professor, Psychiatry and Human Behavior

Director, Psychiatric Education

Irvine Medical Center

University of California

101 City Drive South

Orange, CA 92668

180
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