245

Substance Abuse Among Women:

Familial Factors and Comorbidity

Kathleen R. Merikangas, Ph.D., and Denise E. Stevens, Ph.D.

INTRODUCTION

There is a substantial body of literature on the role of familial factors

in substance abuse; however, most current knowledge has been derived

from studies that focus exclusively on alcoholism. In general, there is

a relative paucity of literature on familial factors and other drug abuse.

In addition, there is a dearth of evidence about the role of genetic

factors in substance abuse among females because of the small numbers

of women in most studies. This chapter (1) reviews epidemiologic

evidence regarding sex differences in the prevalence of substance abuse,

(2) examines whether these sex differences can be attributed to genetic

factors, and (3) investigates the role of psychiatric comorbidity in sex

differences in substance use disorders.

SEX DIFFERENCES IN THE EPIDEMIOLOGY

OF SUBSTANCE ABUSE AND DEPENDENCE

Epidemiologic Studies

Several large-scale community-based studies of psychiatric disorders

have been conducted in the United States over the past several decades.

The Epidemiologic Catchment Area (ECA) Study (Robins and Regier

1991; Kessler et al. 1996) was a landmark investigation conducted

during the early 1980s with the chief goal of estimating the prevalence

of psychiatric disorders in five large regions in the United States.

The National Comorbidity Survey (NCS) (Kessler et al. 1996), which

followed the ECA by almost a decade, is based on a national, stratified,

multistage area probability sample of noninstitutionalized adults (Kessler

et al. 1994). The major differences between these two surveys are the

national sampling frame of the NCS compared with the five-site design

of the ECA; the use of the criteria of the Diagnostic and Statistical Manual

of Mental Disorders, Third Edition, Revised (DSM-III-R) (American

Psychiatric Association 1987) in the NCS rather than the Diagnostic and
246

Statistical Manual of Mental Disorders, Third Edition (DSM-III) (American

Psychiatric Association 1980); more indepth probing by the NCS of

psychiatric symptoms endorsed by the subjects; and a more sensitive

probing method used to reduce recall errors in the NCS.

Table 1 presents the rates of substance use disorders by sex for both

the ECA and NCS. In general, the rates of substance use disorders were

higher among males than females (Anthony and Helzer 1991; Helzer et

al. 1991; Kessler et al. 1994); however, the overall rates of all disorders

were substantially higher in the NCS study. These studies reveal that

although drug abuse and dependence are more common among men

than among women, the sex ratio for drug abuse is closer to equal than

that for alcoholism (Regier et al. 1990b; Warner et al. 1995). There is

an average twofold to threefold excess of males relative to females with

alcoholism compared with a 1.5-fold to twofold excess of males with

abuse of other drugs. This difference in the sex ratio is particularly

pronounced for drug dependence, for which there is a nearly equal sex

ratio. Thus, there appears to be an inverse relationship between the

extent of availability of substances and the decrease in the severity of

the threshold of problematic substance use and sex differences in substance use disorders; that is, the male excess is greatest for use of widely

available substances and least for dependence on “harder” drugs (e.g.,

cocaine or opioids).

The age-specific distribution of drug dependence also differs between

men and women. Epidemiologic data have demonstrated that there is a

greater decrement in the cumulative probability of the development of

TABLE 1. Rates per 100 of substance use disorders, by sex

Epidemiologic National

 Catchment Comorbidity

Area Study Survey

Males Females Males Females

Alcohol abuse 10.3 1.8 12.5 6.4

Alcohol dependence 2.7 0.5 20.1 8.2

Alcohol abuse and dependence 10.9 2.3 — —

Other drug abuse 3.8 2.1 5.4 3.5

Other drug dependence 4.5 2.6 9.2 5.9

Other drug abuse and dependence — — 35.4 17.9
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drug dependence among males than among females who use drugs,

thereby indicating that the risk period for women is longer than for men

(Warner et al. 1995). This has important implications for treatment and

prevention in women; although there is a relatively equal age at onset of

drug dependence for both sexes, the risk period for that onset extends to

midlife in women.

SEX DIFFERENCES IN FAMILY AND GENETIC

STUDIES OF SUBSTANCE ABUSE

Background

The familial aggregation of alcoholism has been well established

(for comprehensive reviews, see Merikangas and Gelernter [1990] and

McGue [1994, pp. 1-40]). On average, controlled family studies of

probands with alcoholism reveal an approximate threefold increased risk

of alcoholism and a twofold increased risk of other drug abuse among the

relatives of probands with alcoholism compared with those of controls.

Several family studies that used information obtained from the proband

(Hill et al. 1977; Meller et al. 1988) and uncontrolled family studies

with direct interviews or questionnaires used to assess relatives (Scherer

1973; Annis 1974; Croughan 1985, pp. 18-33; Mirin et al. 1991;

Rounsaville et al. 1991a; Gordon 1994) suggest that there is a strong

degree of familial clustering of drug disorders as well. However, much

of the evidence on the familial aggregation of drug abuse is taken from

family studies that have not used contemporary family study methods,

including systematic ascertainment of probands, independent enumeration and blind assessment of relatives, application of standardized

diagnostic methods, and a control or comparison group with comparable

information on relatives.

To date, there are only two family studies of drug abusers in which

relatives were interviewed directly (Mirin et al. 1991; Rounsaville et al.

1991a) and only one family study with a non-drug-abusing control group

(Rounsaville et al. 1991a).

Sex Differences in the Familial Aggregation of

Substance Abuse

Most family and genetic studies of alcoholism have focused exclusively on males. However, several family, twin, and adoption studies
248

have demonstrated sex-specific patterns of transmission of alcoholism

(Cloninger et al. 1978; Hill and Smith 1991). One review of evidence

for genetic mediation of alcoholism in women concluded that genetic

factors appear to operate similarly in males and females. However, the

authors underscore the need for studies with sufficient numbers of female

probands (Hill and Smith 1991).

Only two published studies have investigated twin concordance for

drug abuse or dependence in a large series of twins (Pickens et al. 1991;

Jang et al. 1995); however, some studies have examined twin concordance for patterns of alcohol use among women (Heath et al. 1989).

Although concordance rates are greater in female monozygotic pairs

than in dizygotic pairs, few studies have had a sufficient number of

female twin pairs to yield conclusive evidence regarding the heritability

of drug abuse. Pickens and associates (1991) found that both male and

female monozygotic twin pairs had a 1.5-fold increased risk of drug abuse

compared with dizygotic pairs, but the heritability of drug abuse was

significant only for males, possibly because of the low number of female

pairs with drug abuse. Sex differences in the components of genetic and

environmental factors also emerged; the concordance for males could be

attributed to both shared genes and environmental factors, whereas for

females, the majority of variance was attributable to the unique environmental experiences of individual twins. Thus, no evidence for direct

influence of genes on the development of drug dependence in women

has been established. Evidence from adoption studies has been somewhat conflicting in terms of sex differences. Whereas Grove and

colleagues (1990) reported greater heritability of drug abuse among

males, Cadoret and coworkers (1995, 1996) reported equivalent genetic

pathways underlying substance abuse among males and females.

In addition to providing evidence about the possible role of transmissible genetic factors, family studies can be used to investigate sources

of a sex difference in the prevalence of a particular disorder. If the sex

difference can be attributed to genetic factors, familial aggregation data

should reveal an increased risk of this condition among relatives of the

less frequently affected sex (Merikangas et al. 1985). That is, if there is

greater loading for the genetic factors that contribute to the expression

of a particular disorder in one sex, relatives of an index person also

should manifest these factors at a much greater frequency than those of

the more frequently affected sex because the threshold is lower. Family
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study data have been used to investigate sex differences in birth defects,

pyloric stenosis, and stuttering (Falconer 1965; Kidd and Spence 1976;

Pauls and Kidd 1981, pp. 331-362). A sex-specific transmission model

was first applied to alcoholism by Cloninger and colleagues (1978). This

chapter applies family study data to investigate sex differences in the

transmission of substance abuse.

SEX DIFFERENCES IN COMORBIDITY OF

SUBSTANCE ABUSE AND PSYCHIATRIC DISORDERS

The term “comorbidity,” introduced by Feinstein (1970), refers to

the presence of any additional coexisting ailment in a patient with a

particular index (i.e., primary) disease. Nonrandom co-occurrence of

two conditions may be attributable to several methodologic artifacts,

including samples selected from clinical settings that are nonrepresentative of persons with the index disease in the general population (i.e.,

“Berkson’s Paradox”) (Berkson 1946); assessment bias, in which the cooccurrence of two conditions is an artifact of overlap in the diagnostic

criteria or in the assessments used to ascertain the criteria; and the lack

of an appropriate comparison or control group with which to account

for factors that confound the association between the two conditions.

Clinical Studies

The prevalence of psychiatric illness among people in treatment for

substance abuse is high (Penick et al. 1988; Rounsaville et al. 1991a).

Several studies have found high rates of comorbidity between alcoholism

and anxiety disorders (Woodruff et al. 1972; Ross et al. 1988; Regier et

al. 1990a, 1990b; Schuckit et al. 1990), affective disorders (Merikangas

and Gelernter 1990), and antisocial personality disorder (Woodruff et al.

1979, pp. 14-27; Powell et al. 1982; Schuckit 1983a, 1983b, 1983c;

Robins et al. 1988, pp. 15-30) among adults in treatment for alcoholism.

Similarly, substance abuse and dependence in general have been shown

to be strongly comorbid with major depression, bipolar disorder, antisocial personality disorder, and anxiety disorders in samples of clinically

treated adults addicted to cocaine and opioids (Chitwood and

Morningstar 1985; Gawin and Kleber 1986; Griffin and Friedman 1986;

Weiss et al. 1988; Rounsaville et al. 1991a, 1991b; Luthar and

Rounsaville 1993).
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Relatively few studies have focused specifically on the comorbidity

between substance use disorders and psychopathology among females.

In a sample of 100 treatment-seeking people who abused substances,

Brady and colleagues (1993) reported more overall comorbid diagnoses

among females than among males. This elevation in rates was particularly evident among women with anxiety disorders, although the rates

were not substantially different from those of population-based norms.

In contrast, males in this sample showed higher rates of affective disorders. There were no differences by sex for the Axis II disorders (American Psychiatric Association 1987). Likewise, Hesselbrock and coworkers (1985) reported increased rates of panic, depression, and phobic

disorders among females who were in treatment for alcoholism.

Epidemiologic Studies

In both the ECA and NCS, substantial comorbidity was observed

between many of the DSM-III (American Psychiatric Association 1980)

and DSM-III-R (American Psychiatric Association 1987) Axis I psychiatric disorders and both alcoholism and other drug abuse. The ECA

revealed that more than 50 percent of people who abused substances

also had at least one mental disorder, with lifetime prevalence ratios

of 28 percent for anxiety disorders, 26 percent for affective disorders,

18 percent for antisocial personality disorder, and 7 percent for schizophrenia (Regier et al. 1990a).

An examination of the prevalence rates of disorders comorbid with

substance use disorders reveals that both substance abuse and dependence are highly comorbid with antisocial personality disorder, anxiety

disorders, and affective disorders, irrespective of sex (Regier et al. 1990a,

1990b; Anthony and Helzer 1991; Helzer et al. 1991; Kessler et al.

1996). Table 2 presents the prevalence ratios among males and females

for a number of DSM-III diagnoses comorbid with substance use disorders from the ECA. Although the rates of all disorders among females

with alcoholism or other drug abuse are greater than those for population base rates, the rates are particularly elevated for antisocial personality disorder, mania, and schizophrenia. That is, when a female is alcoholic or drug dependent, she is more likely than a male to exhibit

concomitant antisocial personality disorder (Helzer and Pryzbeck 1988;

Helzer et al. 1991). Helzer and Pryzbeck (1988) also have reported a

sex differential in which alcoholic females were far more likely than
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alcoholic males to have a diagnosis of major depression when compared

with population rates of the United States at large. Furthermore,

females with alcoholism were more likely to report that onset of depression followed that of alcoholism, whereas males with alcoholism were

more likely to report that the onset of depression preceded that of

alcoholism. The high magnitude of comorbidity between substance

abuse and psychopathology in this large-scale community survey suggests

that the frequent co-occurrence of these conditions reported from

clinical samples is not simply an artifact of sampling bias.

Familial and Genetic Studies

Although much research has addressed the familial patterns of

alcoholism and other drug abuse, the familial patterns of comorbidity

among people who abuse substances have received scant attention,

particularly with regard to sex differences. Application of the family

study paradigm to elucidate mechanisms for comorbidity requires

probands selected for the presence or absence of the comorbid disorder

under study as well as suitable controls that use ascertainment and

TABLE 2. Comorbidity of substance abuse or dependence and other

psychiatric disorders: Prevalence ratios from the

Epidemiologic Catchment Area Study

Females Males

Alcohol Other Drug Alcohol Other Drug

Abuse/ Abuse/ Abuse/ Abuse/

Dependence Dependence Dependence Dependence

Antisocial 29.6* 26.6* 12.0 7.3

Alcoholism — 9.0* — 2.9

Other drug abuse/

 dependence 8.8* — 4.8 —

Major depression 2.7 3.6 2.4 4.9

Mania 9.3 11.1 6.5 11.3

Dysthymia 2.2 3.1 2.5 5.1

Panic 4.4 2.9 4.2 4.1

Phobias 2.1 1.9 1.8 2.4

Obsessive compulsive

 disorder 2.1 3.5 3.0 3.6

Schizophrenia 5.6 6.4 4.6 6.2

*Significantly greater than comorbidity rates among males
252

assessment methods comparable to those used with the probands. The

lack of consistent methodology in previous family studies of drug abuse

limits their ability to address adequately the cosegregation of substance

use disorders and psychopathology.

Several studies have used family history data to examine the etiologic overlap between alcoholism and other drug abuse. Hill and

colleagues (1977) concluded that alcoholism and opioid abuse were

transmitted independently; likewise, Meller and coworkers (1988)

demonstrated specificity of transmission of alcoholism and other drug

abuse among relatives of probands with substance abuse.

Numerous family history studies and systematic family studies of

substance abusers in treatment settings (Hill et al. 1977; Croughan

1985, pp. 18-33; Gfroerer 1987; Meller et al. 1988; Mirin et al. 1988,

1991; Rounsaville et al. 1991a) have reported a significantly higher risk

for both alcoholism and other drug abuse among relatives of people who

abuse substances than among the general population. Rounsaville and

colleagues (1991a) reported a sex difference in comorbidity among

relatives of people who abuse substances. That is, there were higher

rates of alcoholism, other drug abuse, and antisocial personality disorder

among the male relatives of people addicted to opioids, whereas anxiety

and affective disorder rates were elevated among the female relatives of

people who abused substances. However, these findings are suggestive

at best because of the lack of adequate evidence from family studies that

use contemporary family study methodology, particularly control groups,

in investigating familial patterns of drug abuse.

Recent family studies by Merikangas and colleagues (1994), Maier

(1993), and Maier and Merikangas (1996) investigated the familial

patterns of comorbidity between the affective disorders, anxiety disorders, and alcoholism. On the basis of an elevated risk of alcoholism

among the relatives of probands with pure panic disorder, patterns of

cosegregation of alcoholism, depression, and anxiety disorders among

relatives of probands—with each of these conditions compared with

controls—suggested some degree of shared susceptibility factors for

alcoholism, panic, and depression. These results were confirmed in a

recent uncontrolled family study of anxiety disorders that also suggested

an etiologic relationship between anxiety disorders and substance abuse

(Skre et al. 1994).
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Aside from their traditional goal of discriminating between the roles

of genetic and environmental factors and their interaction in the

development of a disorder, adoption studies also have been informative

in examining the links between substance abuse and psychopathology.

The classic adoption studies of Cadoret and coworkers (Cadoret 1992,

pp. 99-113; Cadoret et al. 1985) identified two major biologic or genetic

pathways to the development of drug abuse in adoptees: One is driven

by substance abuse in the biologic parent and is limited to drug abuse

and dependence in the adoptee, and the other appears to be an expression of underlying aggressivity and to be related to criminality in the

biologic parent (Cadoret et al. 1995). Recently, these researchers

extended their findings to include a female sample of adoptees, who over

the longitudinal course were found to manifest a genetic pathway similar

to that of males: A biologic parent with antisocial personality disorder

was associated with the development in the offspring of conduct problems in adolescence and aggressivity and substance abuse problems in

adulthood (Cadoret et al. 1996).

YALE FAMILY STUDY

The remainder of this chapter presents the results of the authors’

large-scale family study, which was specifically designed to examine the

mechanisms for comorbidity among alcoholism, other drug abuse, and

anxiety disorders, as well as sex differences in the transmission of substance abuse/dependence. Comorbidity and cotransmission of marijuana

abuse or dependence and anxiety disorders were examined to investigate

the nature of the relationship between these disorders. The risk of

marijuana abuse or dependence was assessed among 1,215 adult firstdegree relatives of 260 probands with marijuana abuse or dependence,

alcohol abuse or dependence, and anxiety disorders and among normal

controls. These probands were ascertained from either treatment

settings or the community through a random digit dialing procedure.

The methods of this study are detailed elsewhere (Merikangas et al.

1996, in press). Preliminary findings revealed a lack of shared underlying factors in the familial transmission of alcoholism and other drug

abuse.

The sample consisted of three groups: (1) 36 probands with marijuana or sedative abuse or dependence, (2) 88 probands with alcohol
254

abuse or dependence, and (3) a psychiatric control group composed of

76 subjects with anxiety disorders and 60 subjects without DSM-III-R

diagnoses. The probands are described in table 3. Although equal

proportions of male and female probands were in the marijuana or

sedative group, there were approximately twice as many males in the

alcohol group and twice as many females in the control group. There

were no differences among the three groups with respect to age; however, a larger proportion of probands in the alcohol and marijuana/

sedative groups were divorced and were from a lower socioeconomic

group. Similarly, both the alcohol and the marijuana/sedative groups

had significantly lower global assessment of functioning scores compared

with the control group. The number of relatives within each proband

group is noted at the bottom of the table.

A diagnostic description of the probands revealed that, with respect

to anxiety disorders, panic with agoraphobia was higher in both the

marijuana/sedative and control groups than in the alcohol group. In

contrast, agoraphobia without panic was higher in the alcohol group

than in the marijuana/sedative and control groups. All the affective

disorders (major depression, bipolar disorder, and dysthymia) were

significantly higher in the alcohol and marijuana/sedative groups than

in the control group. The majority of marijuana/sedative abuse/dependence probands also had a lifetime history of alcohol abuse/dependence.

There were significant differences between the groups with respect to

TABLE 3. Yale Family Study of specificity of transmission of substance

use disorders: Description of the sample

Diagnoses of Probands

Marijuana or Sedative Alcohol Abuse Psychiatric

Abuse or Dependence or Dependence Control Group

Probands (N=36) (N=88) (N=136)

Male (percent) 58 70 34

Age (mean) 36 40 40

Socioeconomic status

 (percent Hollingshead>3) 94 81 57

Married (percent) 64 57 88

Global assessment of

 functioning (mean) 61 62 76

Number of relatives 185 414 619
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rates of current diagnoses of marijuana/sedative abuse or dependence and

alcohol abuse/dependence; however, there were no differences in the

rates of current anxiety disorders. Antisocial personality disorder was

significantly higher in both the marijuana/sedative and alcohol groups

than in the control group.

Table 4 presents the rates of substance use disorders among relatives

of probands according to the sex of the relative. There was specificity of

both alcohol abuse/dependence and marijuana/sedative disorders, with a

significant increase in the rates of marijuana/sedative abuse/dependence

among both male and female relatives of probands with marijuana/

sedative abuse/dependence. There were sex differences in the prevalence rates of alcohol disorders, particularly alcohol dependence, with

the rate for males twice that for females. Although males had higher

rates of marijuana/sedative disorders, the differences by sex for dependence for marijuana/sedative disorders were not significant. Whereas

relatives of probands with marijuana/sedative dependence had elevated

rates of alcohol abuse/dependence, relatives of probands with alcohol

abuse/dependence did not have significantly elevated rates of marijuana/

sedative disorders. This finding suggests some degree of specificity in the

familial aggregation of marijuana/sedative disorders. Across all proband

TABLE 4. Yale Family Study of specificity of transmission of substance

use disorders: Rates per 100 of substance use disorders in

relatives

Diagnoses of Probands

Marijuana or Alcohol

Sedative Drug Abuse or Psychiatric

Disorders Dependence Control Group

(N=185) (N=414) (N=619)

Diagnosis in Relatives Male Female Male Female Male Female

Alcohol abuse 7.5 12.0 15.6 9.1 12.9 6.5

Alcohol dependence 41.9 9.8 34.1 13.9 17.1 5.5

Alcohol abuse and

 dependence 48.4 21.7 48.8 22.5 28.7 11.3

Marijuana/sedative abuse 16.1 7.6 10.2 2.9 4.8 2.3

Marijuana/sedative

 dependence 11.8 8.7 3.9 2.9 3.6 2.3

Marijuana/sedative abuse

 and dependence 22.6 15.2 13.7 5.3 7.4 4.2
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groups, the rates of alcohol dependence among male and female relatives

were much higher than those of alcohol abuse. As was observed with

alcohol abuse, increased rates of alcohol dependence were observed

among both the male and female relatives of probands with marijuana/

sedative abuse or dependence or with alcohol abuse/dependence. Essentially the same pattern of results was observed when examining the

specificity of transmission of marijuana/sedative abuse or dependence

among the relatives of probands with marijuana/sedative abuse or

dependence. That is, increased rates of marijuana/sedative abuse and

dependence were observed among the male and female relatives of

probands with either marijuana/sedative or alcohol problems. However,

in contrast to the findings with alcohol abuse and dependence, the

increased rates of marijuana/sedative abuse and dependence were

specific to the female relatives of probands with marijuana/sedative

abuse or dependence and were not specific to alcohol abuse/dependence.

Table 5 presents the rates of marijuana/sedative abuse/dependence

according to sex of the proband and sex of the relative. Consistent with

previous epidemiologic and family genetic studies, there was a twofold

risk of substance abuse or dependence among the male relatives of

probands with substance abuse or dependence compared with their

female proband relatives (40.5 v. 19.0 percent, respectively). In contrast, there were approximately equal rates of substance use disorders

among the relatives of male and female probands with substance use

disorders.

TABLE 5. Yale Family Study of specificity of transmission of substance

use disorders: Rates per 100 of marijuana/sedative abuse

or dependence among relatives, by sex of proband and sex

of relative

Marijuana/Sedative Abuse/Dependence

Probands Males Female Total

Relatives:

Marijuana/sedative abuse or dependence

 Males (n=608) 40.1 40.8 40.5

 Females (n=610) 15.9 22.0 19.0

 Total (n=1,218) 28.2 31.3 29.7
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Table 6 presents sex-specific comorbidity odds ratios (ORs) for

marijuana/sedative abuse or dependence and psychiatric disorders among

relatives. These odds ratios were adjusted for age, history of alcoholism,

and interview status (sex also was controlled for in the total sample).

A significant degree of comorbidity existed between alcoholism and

marijuana/sedative abuse/dependence disorders, anxiety, affective

disorders, and antisocial personality disorder. Although there were no

aggregate sex differences in the patterns of comorbidity of marijuana/

sedative abuse/dependence and other conditions reported in table 6,

investigation of specific subtypes of these disorders revealed some sex

differences in comorbidity. With respect to anxiety disorders, panic

and marijuana/sedative abuse/dependence disorders were significantly

comorbid among females (OR=3.2) but not among males (none of the

only seven male cases of panic disorder had a comorbid drug use disorder). Generalized anxiety disorder was significantly associated with

marijuana/sedative abuse/dependence disorders among both males and

females, whereas there was no significant association between drug use

disorder and either social phobia or agoraphobia. All affective subtypes

were elevated among both the male and female relatives with alcohol

and other drug use disorders.

TABLE 6. Yale Family Study of specificity of transmission of substance

use disorders: Comorbidity of psychiatric disorders among

male and female relatives (adjusted for age and interview

status)a,b—odds ratios (±95 percent confidence limits)

Marijuana/Sedative Marijuana/Sedative

Abuse/Dependence Abuse/Dependence

Disorder Males Females Total

Alcoholism 10.6 (5.2-21.5)* 9.9 (4.3-23.1)* 10.5 (6.0-18.4)*

Anxietyc 2.6 (1.2-5.2)† 2.0 (0.8-4.9) 2.4 (1.3-4.2)‡

Affectived 2.5 (1.3-4.9)‡ 3.6 (1.4-9.1)‡ 3.0 (1.7-5.2)*

Antisocial personality 5.1 (1.9-13.5)‡ 11.1 (2.5-49.4)‡ 6.0 (2.7-13.5)*

aFor antisocial personality disorder, anxiety, and affective disorders, alcohol status was

controlled for in analyses.

bFor “total” analyses, the sex of relative also was controlled for.

c

Includes panic, generalized social phobia.

d

Includes bipolar disorder, major depression, dysthymia.

*p<0.001

†p<0.05

‡p<0.01
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Table 7 presents the results of multivariate modeling of the association between drug use disorders among probands and relatives after

controlling for comorbidity and demographic factors. The results reveal

specificity of transmission of marijuana or sedative use disorder

(OR=3.6, p<0.001). There was no evidence of cross-transmission

involving proband alcohol dependence or anxiety disorders. With

respect to comorbidity among relatives, anxiety disorders in general were

associated with substance use disorders among male (OR=2.4, p<0.05)

but not among female relatives, whereas the affective disorders were

more strongly associated among females. Antisocial personality disorder

was highly comorbid with substance use disorders among both male and

female relatives.

TABLE 7. Yale Family Study of specificity of transmission of substance

use disorders: Comorbidity and cotransmission of

marijuana/sedative abuse or dependence and comorbid

disorders among probands and relatives

Drug Abuse/Dependence

Disorders/Covariates Males Females All

Disorders in probands

 Marijuana/sedative abuse

 or dependence v. none 4.0* 2.9† 3.6*

 Alcohol dependence v. none 1.2 1.3 1.2

 Anxiety, all 0.7 0.2‡ 0.5‡

 Affective, all 1.1 5.0§ 1.4

 Antisocial personality disorder 0.9 — 0.6

Disorders in relatives

 Alcohol dependence v. none 7.2* 3.8§ 5.8*

 Anxiety, all 2.4‡ 1.4 2.0‡

 Affective, all 2.1‡ 5.0§ 2.7§

 Antisocial personality disorder 4.7§ 11.6§ 5.4*

Covariates for relatives

 Interview v. none 0.7 0.8 0.7

 Age 0.9* 0.9§ 0.9*

 Female v. male — — 0.5‡

Covariates for probands

 Female v. male 1.3 1.5 1.4

*p<0.001

†p<0.10

‡p<0.05

§p<0.01
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DISCUSSION

Explanations for the Differences by Sex

in Drug Abuse or Dependence

Numerous possible explanations exist for the differences by sex

observed in the prevalence rates of substance use and psychiatric disorders. The differences by sex in affective disorder have been studied

extensively (Weissman and Klerman 1977). Possible methodologic

explanations such as reporting bias in women, as well as differences by

sex in biologic, genetic, and sociocultural factors, have been considered

as the chief sources of the female preponderance of depression. In

general, the evidence suggests that the sex differences in depression are

not an artifact of sampling or an increased tendency to report depressive

symptoms in women, nor do they appear to result from increased genetic

loading in women (Merikangas et al. 1985). Thus, the most likely

sources of the sex differences in depression are a combination of biologic

(e.g., neuroendocrine-triggered changes in the neurochemical factors

underlying depression), psychological (e.g., different cognitive styles of

women), and sociocultural factors (e.g., social role factors).

Epidemiologic data cited in this chapter suggest that women have

lower rates of drug abuse than men. Application of family study data to

examine whether the sex differences in drug abuse can be attributed to

more genetic loading in women than men, according to the model

developed by Cloninger and colleagues (1978), revealed that genetic

factors are not the likely source of sex differences in drug abuse. Therefore, other explanations need to be explored. A review by el-Guebaly

(1995) suggests several possible explanations for sex differences in drug

abuse, including sex-specific biologic mechanisms, psychological vulnerability, and sociocultural factors.

Although some studies reveal increased concordance rates between

same-sex parent-child pairs (i.e., mother-daughter, father-son) (Annis

1974), systematic family studies do not reveal greater familial aggregation of substance abuse among the relatives of female substance abusers

than among male substance abusers (Mirin et al. 1991; Rounsaville et al.

1991b). The lack of sex differences in transmission of drug abuse

observed in the Yale Family Study confirms this suggestive evidence but

is far more conclusive than the evidence from previous studies because

of the inclusion of a control group in the study design. The lack of sex

differences in familial aggregation of substance abuse suggests similar
260

underlying genetic factors in the etiology of drug disorders among men

and women. Therefore, sex differences are most likely a manifestation

of either biologic or psychosocial factors that serve as a protective

influence in women or enhance the development of substance abuse

among men. Such factors could operate at the level of exposure or in

the transition between use and abuse.

Comorbidity: One Mechanism for

Familial Transmission of Substance Abuse?

In addition to genetic factors underlying metabolism and biologic

and psychological effects of drugs, psychiatric disorders may be one of

the transmissible familial factors that elevates the risk of drug abuse

among relatives of substance abusers, particularly among women.

Sex Differences in Patterns of Comorbidity of

Substance Use Disorders and Psychopathology

In general, patterns of comorbidity of substance abuse and psychopathology are equivalent for men and women. However, studies of clinical

samples have shown that comorbidity of affective disorders is more common among male substance abusers than population expectations and

that comorbidity of both affective and anxiety disorders is greater among

female cocaine abusers than rates of comorbidity in epidemiologic

studies (Brady et al. 1993). Most clinical research has focused on comorbidity of drug abuse with other manifestations of externalizing disorders

such as antisocial personality disorder and alcoholism. Far less attention

has been addressed to the comorbidity between internalizing problems

such as depression or anxiety and substance abuse. The results of several

clinical and epidemiologic studies reveal that affective and anxiety

disorders are strongly associated with drug abuse among both sexes

(Helzer and Pryzbeck 1988; Regier et al. 1990b; Kessler et al. 1996).

Investigation of specific subtypes of internalizing disorders yields

some interesting sex differences in the role of primary disorders underlying the development of substance abuse. Epidemiologic and clinical

studies reveal that bipolar affective disorder has the greatest association

with drug abuse of all disorders in general and with individual subtypes

of affective disorder specifically (Regier et al. 1990b; Brady and Sonne

1995).
261

The results of the Yale Family Study suggest that comorbidity of

bipolar affective illness and substance abuse appears to be particularly

elevated among women. The phobic disorders, particularly social

phobia, are the subtypes of anxiety most strongly associated with substance abuse (Amies et al. 1983; Kushner et al. 1990; Regier et al.

1990b; Merikangas and Angst 1995; Kessler et al. 1996). Although the

results of the Yale Family Study reveal a strong association between

phobic states and substance abuse, the phobic disorders appear to

increase the risk of drug abuse specifically among men.

Familial Patterns of Substance Abuse

And Comorbid Psychopathology

The results of family studies of probands with different primary drugs

of abuse, including opiates, cocaine, and marijuana (Hill et al. 1977;

Meller et al. 1988; Mirin et al. 1991; Rounsaville et al. 1991b), suggest

that the familial transmission of alcoholism and other drug abuse is

independent. Several of the family studies of drug abuse also have

investigated the degree to which comorbid disorders among people who

abuse substances are associated with drug use and psychiatric disorders

among their relatives. In general, results suggest that substance abuse

and comorbid disorders are transmitted independently among relatives.

That is, rates of affective disorders, antisocial personality, and anxiety

disorders are elevated among the relatives of probands with these

comorbid disorders themselves (Mirin et al. 1991; Rounsaville et al.

1991b). The data from the Yale Family Study support these findings

regarding the lack of evidence of cosegregation of psychiatric disorders

and substance abuse. Thus, although substance abuse and comorbid

disorders tend to co-occur in individuals, they do not represent alternative manifestations of the same underlying etiologic factors in families.

Comorbid psychiatric disorders could either be a cause or a consequence

of drug abuse.

Role of Comorbid Disorders in the

Development of Substance Abuse

Studies of the order of onset of drug abuse and psychiatric disorders

tend to reveal consistent patterns of association between the externalizing and internalizing disorders in general and the development of drug
262

use and abuse in particular. Use and abuse of drugs appear to be part of

a generalized pattern of deviant behavior with little specificity in the

choice of specific substance of abuse (Jessor and Jessor 1977). Females

with conduct problems and antisocial behavior tend to exhibit patterns

of substance use and abuse similar to those of men (Robins and Price

1991). Moreover, the role of externalizing disorders, particularly conduct problems and aggressivity, in precipitating the use and abuse of

drugs appears to be equivalent among males and females. Cadoret and

colleagues (1995, 1996) have shown that this is the major pathway

through which genes exert their influence on the development of drug

abuse among both men and women.

Role of Longitudinal Studies in

Establishing Causal Mechanisms

Longitudinal studies are important for the elucidation of causal

relationships between disorders, the identification of common risk

factors and their sequelae, and the discovery of homogeneous subtypes

that may vary according to the stability of patterns of expression across

the longitudinal course. Longitudinal studies of children have focused

primarily on boys where the sequelae of conduct and behavior problems

have been examined (Loeber 1982). However, conduct disorder is also

clearly evident among girls, and the disproportionate attention to boys

may result in a sex bias in the diagnostic criteria for identifying girls

(Zoccolillo and Rogers 1991).

Retrospective data suggest that the pathways toward substance abuse

can vary by sex. Conduct problems among girls are directly associated

with the subsequent development of depression or anxiety, followed by

alcohol or other drug abuse that appears to result from self-medication

for depression, whereas among boys there is a more direct link between

early behavior problems and antisocial behavior coupled with substance

abuse (Robins and Regier 1991). A latent class analysis of problem

behavior among teenagers that used prospective data from the New

Zealand birth cohort study revealed that female problem behavior was

likely to begin with accelerated transition to adult hedonic behaviors,

including early sexual activity and use of alcohol and other drugs,

whereas males tended to manifest a more generalized pattern of antisocial behavior (Fergusson et al. 1994). These findings indicate a clear

need for prospective studies of girls at high risk for behavior problems.
263

The other major pathway for the development of substance use

disorders is through the association between substance use and internalizing disorders. Data from the Yale Family Study suggest that bipolar

affective disorder and social phobia appear to be the chief subtypes of

depression and anxiety that lead to the development of substance abuse.

In contrast, although both panic disorder and major depression appear

to be associated with substance abuse, they appear to have no systematic

role in precipitating the use or abuse of alcohol or other drugs. Weiss

and coworkers (1992) have described the importance of the role of drugs

in treating the manifestations of psychiatric symptoms and disorders.

Therefore, self-medication of the early manifestations of the affective

dysregulation present in bipolar disorder or the social anxiety that

underlies social phobia is a likely explanation for the strong degree of

comorbidity between these two subtypes of affective and anxiety disorders and substance abuse. Thus, women with either of these conditions,

or even those at high risk for their development by virtue of a positive

family history, should be an important target group for prevention

efforts.

The consistency of the patterns of comorbidity (e.g., depression,

anxiety, antisocial personality disorder) among the various substance use

disorders has important implications for the development of treatment

strategies, particularly when the onset of the conditions predates the

substance abuse. Early prevention and intervention strategies should

prove efficacious if the target populations are identified before the onset

of illness. Weisner and Schmidt (1992) and Anthenelli and Schuckit

(1993, pp. 73-87) have shown that the course of disease and treatment

outcome are more complicated for substance abuse with comorbidity

than for uncomplicated substance abuse and that women may have a

worse course than men.

SUMMARY

The complex problem of psychiatric comorbidity among substance

abusers and the implications for treatment are poorly understood. Scant

attention has been paid to the role of comorbidity in discriminating sex

differences during the course of treatment for women. Additional work

is needed, particularly on identifying the causes of sex differences in drug

abuse. Although the results of the Yale Family Study demonstrate a lack

of genetic factors in the etiology of the sex differences in drug abuse,
264

confirmation in other samples is necessary. The results of this study

suggest that examining mechanisms of comorbidity through the use

of family study methodology and longitudinal studies serves as an

important stepping-stone toward understanding the causes of sex differences in substance abuse.

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ACKNOWLEDGMENTS

This work was supported in part by grants AA-07080, DA-09055,

DA-05348, and MH-36197 from the Alcohol, Drug Abuse, and Mental

Health Administration of the U.S. Public Health Service and Research

Scientist Development Awards from the National Institute of Mental

Health (K02 MH-00499 and K02 DA-00293).

AUTHORS

Kathleen R. Merikangas, Ph.D.

Professor of Epidemiology and Psychiatry

Departments of Psychiatry and Epidemiology

kathleen.merikangas@yale.edu (E-mail)

Denise E. Stevens, Ph.D.

Associate Research Scientist

Department of Epidemiology

denise.stevens@yale.edu (E-mail)

Genetic Epidemiology Research Unit

Yale University School of Medicine

40 Temple Street, Suite 7B

New Haven, CT 06510-3223

(203) 764-9740 (Tel)

(203) 764-9739 (Fax)