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Alcoholism and depressive disorders in opioid addicts and their family members
Alcoholism and Depressive Disorders in Opioid Addicts and Their Family Members Thomas R. Kosten, Therese A. Kosten, and Bruce J. Rounsaville The co-occurrence of alcoholism and depression was examined in 201 opioid addicts and their 877 first-degree relatives using direct interviews and structured family history based on the Schedule for Affective Disorders and Schizophrenia (SADS) Research Diagnostic Criteria (RDC) method. Familial alcoholism was more frequent in alcoholic than nonalcoholic proband addicts, and primary depression was more frequent in relatives of depressed than nondepressed addicts. An association was suggested between secondary, but not primary, depression and alcoholism in females. Copyright G 1991 by W.B. Saunders Company
D
EPRESSIVE DISORDERS are common among both alcoholics and opioid addicts,‘,2 as well as among their relatives,‘~’ suggesting a familial relationship between depression and substance abuse. While the consensus of many studies, as summarized by Schuckit,’ has been that alcoholism and primary depressive disorders show independent transmission in families, a recent review by CoryelP has suggested that secondary depression is associated with alcoholism in family members. These secondary depressions are defined in terms of age of onset, and in most substance abusers the age of onset for depression is after the age of onset for the substance dependence. Since there is a large co-occurrence of depression and alcoholism in opioid addicts and their relatives, this association with secondary depression might also be examined among opioid addicts and their first-degree relatives. Coryel? has further suggested that this association may be stronger in females than in males. By comparing rates of alcoholism and of primary and secondary depression in the male and female relatives of our probands, we will examine this gender difference in associations. To facilitate this examination of gender differences, we oversampled female opioid addicts to attain equal proportions of males and females in the proband group. Since the probands have predominantly secondary, not primary, depressive disorders, statistically significant associations for the whole sample will also be examined after excluding probands with primary depression. Comparisons in rates of depression and alcoholism in relatives will be made across four proband groups: (1) depression plus alcoholism, (2) depression alone, (3) alcoholism alone, (4) neither disorder in the proband. In these comparisons, several findings would be consistent with Coryell’s assessment of the alcoholism studies on secondary depression. First, the rates of primary depression in relatives
From the Substance Abuse Treatment Unit, Connecticut Mental Health Center, Depanments of Pvchiatry and Epidemiology Yale University School of Medicine, New Haven, CT. Suppotied by grants from ADAMHA including Center Grants No. P50-DAO4060, ROI-DA03090, and ROI-DA05348 and Research Career Development Awards No. DA00089 to B.J.R. and DA00112 to T.R. K. Address reprint requests to Thomas R. Kosten, M.D., Substance Abuse Treatment Unit. 27 Sylvan Al,e, New Haven. CT 06519. Copyright 0 1991 by W B. Saunders Company 0010-440X/91 132060002$03.00/0 Comprehensive
Psychiatry,
Vol. 32, No. 6 (November/December),
1991: pp 521-527
521
522
KOSTEN, KOSTEN, AND ROUNSAVILLE
will not be associated with proband alcoholism, while secondary depression will be higher in relatives of probands with alcoholism plus depression or with alcoholism alone than in relatives of probands with depression alone. Second, this association of proband alcoholism with relatives’ secondary depression will be stronger in females than in males. Third, alcoholism rates in relatives of probands with depression, which is almost entirely secondary depression, will be increased compared with those relatives of probands without depression, and those relatives of probands with alcoholism plus depression will have the highest rates of alcoholism among the four proband groups. Fourth, this association of relatives’ alcoholism with probands’ secondary depression will be stronger in females than in males. METHOD Overall Study Design This study is a case control design in which white opioid addicts were matched on age and sex for opioid dependence with or without depression. Race was not a matching factor, as all the probands were white. The study was also a family study in which we attempted to interview directly all first-degree relatives and spouses. When direct interviews were not possible, information was determined from family history reports by relatives.
Opioid Addict Probands Adult, white, opioid-addicted probands from the Substance Abuse Treatment Unit of the Connecticut Mental Health Center were interviewed between 1983 and 1985. Opioid dependence was defined as both meeting the Research Diagnostic Criteria (RDC) for opioid dependence and having used opioids regularly for at least 2 years. To identify probands, all white, adult, nonadopted patients who were seeking treatment for opioid dependence (n = 348) were screened for psychiatric diagnosis using the Lifetime Version of the Schedule for Affective Disorders and Schizophrenia (SADS-L).“ Among those screened, 103 (30%) were excluded, because of failure to meet criteria for one of the cells, such as being a depressed female after this cell was already filled, and 42 (12%) refused to participate. The 201 (58%) study participants included a depressed group who met criteria for both opioid dependence and major depression, but did not meet criteria for bipolar illness, schizophrenia, briquet’s disorder, or unspecified functional psychosis. We required that depressive symptoms were not drug-related, as described elsewhere.‘,’
Diagnostic Assessment of Relatives The procedure for making diagnostic assessments of the first-degree relatives used the best estimate technique of Leckrnan et al.“.” For the diagnosis of alcoholism, this technique has shown excellent reliability between evaluators, and validity in comparison to direct interview diagnoses. The 201 opioid-addicted probands identified 879 first-degree relatives, including two fathers on whom no information was available, leaving 877 adult (age 18 and older) relatives. Of these, 234 were interviewed directly, 264 were not interviewed but were diagnosed on the basis of family history information from the proband and at least one additional informant, and 379 were not interviewed, and diagnosis was based on proband report only. For opioid-dependent probands and their families, two psychologists experienced with the diagnostic system made an initial best estimate diagnosis based on review of all available information. For directly interviewed relatives, the SADS-L with RDC criteria was used in an identical procedure to that used for the probands. For those relatives not directly interviewed, the family history RDC developed by Andreasen et al.” was used with structured interviews of the proband and any available relatives in order to collect data for diagnoses. In those cases in which the subject met the criteria for any psychiatric disorder, the records and interviews were reviewed independently by a second diagnostician. Any substantial disagreements between the two diagnosticians were reviewed on a case-by-case basis. The details of the best estimate procedure for the current study are described elsewhere.3
ALCOHOL
523
AND DEPRESSION
Data Analysis We used chi-square analysis to compare groups on rates of familial alcoholism, with logistic regression analysis for multiway contingency tables. In logistic regression, the dependent variable, alcoholism in the relatives of the proband, is given a logistic transformation yielding the logit or log odds ratio. The multiplicative factor by which the odds increase or decrease relative to changes in the predictor variables was then determined.” These predictor variables included relatives’ sex, age, and interview status. The design features of proband diagnostic group and sex were also included in these regression analyses in order to determine the independent association of familial alcoholism with proband alcoholism. Parameters in these logistic models were determined using maximum likelihood estimates. Interaction terms were added to test specific hypotheses, and goodness of fit was considered satisfactory, if the residual likelihood ratio chi-square was not statistically significant.
RESULTS Among the 201 opioid addict probands, 121 (60%) met RDC criteria for alcoholism some time in their lives, and 125 (62%) had been selected, because they met criteria for major depressive disorder. As shown in Table 1, the four proband groups formed by the cross tabulation of depression with alcoholism did not differ in sex, age, social class, religion, or marital status. One hundred eighteen (94%) of the probands had secondary depressions, with the mean age of onset for depression being 21 years (SD 6.0), and for substance dependence being 15 years (SD 2.7) among the 125 depressed probands. The first-degree relatives of the probands included 228 alcoholics (26%) and 139 depressives (16%). Primary depression was determined by selecting depressed relatives whose age of onset for depression preceded substance abuse or who were without alcohol or other drug abuse. Eighty-seven relatives (10% overall or 63% of depressives) had primary depression, and 50 relatives (6% overall) had secondary depressions: 18 due to alcoholism alone, 17 due to drug dependence alone, and 15 due to both disorders. As described in previous publications, both depression and alcoholism in the probands were associated with similar disorders in their first-degree relatives.“” Before examining the co-occurrence of depression and alcoholism in the probands and their relatives, we compared the demographics of the relatives in the four proband groups formed by cross-tabulating proband alcoholism with depression. These four groups did not differ significantly in age, sex, relationship to proband, percent living, or percent interviewed, as shown in Table 2. We first examined depressive disorders in the probands’ relatives, as outlined above. As shown in Table 3, rates of depression were higher in relatives of Table 1. Demographics
of Opiate Addict Probands by Major Depression and Alcoholic Versus Nonalcoholic (n = 201) Alcoholic Probands (n = 121)
Characteristic % Male (n) Age in years (SD) % Married (n) % Class l-3 % Class 4-5
Depressed (n = 84) 46% 28 29% 22% 78%
(39) (4) (24) (18) (66)
Nondepressed (n = 37) 59% (22) (3) :z% (12) 15% (5) 86% (32)
Nonalcoholic Probands (n = 80) Depressed (n = 41) 42% 30 39% 34% 66%
(17) (4) (16) (13) (28)
Nondepressed (n = 39) 44% (17) (4) :Y% (14) 30% (11) 70% (28)
KOSTEN, KOSTEN, AND ROUNSAVILLE
524
Table 2. Demographics
of First-Degree Relatives of Opiate Addicts by Major Depression and Alcoholic Versus Nonalcoholic (n = 877) Relatives of Nonalcoholic Probands (n = 352)
Relatives of Alcoholic Probands (n = 525)
Characteristic
% male (n) Age in years (SD) Relationship % Parent % Sibling % Interview
Proband Depressed (n = 350)
Proband Depressed (n = 175)
Proband Nondepressed (n = 175)
Proband Nondepressed (n = 177)
51% (178) 41 (16)
53% 42
(93) (15)
54% (94) 44 (16)
52% 41
(92) (16)
48% (167) 52% (183) 29% (100)
42% (74) 58% (101) 24% (42)
47% (82) 53% (93) 30% (53)
44% (77) 57% (100) 21% (37)
depressed probands (line l), and this association held for primary (line 2), but not for secondary (line 3), depression. When we examined this distinction between primary and secondary depression by relative and proband gender, the most informative comparison was between the relatives of probands with either depression or alcoholism alone. For example, as shown in lines 8 and 9 for male relatives of female probands, the rate for primary depression was four times higher than for secondary depression in the relatives of probands with depression alone (17% v 4%), while the relatives of probands with alcoholism alone had the converse relationship with higher secondary than primary depression rates (0 v 8%). This same pattern can be seen in the male relatives of the male probands. This pattern is statistically significant for primary versus secondary depression in Table 3. Rates per 100 of Primary and Secondary Major Depressive Disorder in the First-Degree Relatives of Opioid Addicts by Relatives’ and Probands’ Gender (n = 877) Relatives of Alcoholic Probands
Gender Relatives
Probands
All
All
Male
Male
Male
Female
Female
Male
Female
Female
Relatives Depressed ALL Primary Second ALL Primary Second ALL Primary Second ALL Primary Second ALL Primary Second
Relatives of Nonalcoholic Probands
Proband Nondepressed
Proband Depressed
Proband Depressed
Proband Nondepressed
% DEP
(n)
% DEP
(n)
% DEP
(n)
% DEP
(n)
x2
19% 13% 6% 13% 8% 5% 13% 5% 8% 24% 20% 4% 26% 18% 8%
(35)
13% 6%
(175)
(175)
11% 6%
(177)
* t
(87)
1::; 5% 13% 8% 0
(55)
17% 13% 4% 4% 4% 0 21% 17%
(46)
(74)
IZ 11%
(46)
2::; 13%
(38)
IZZ 5% 10% 6% 2% 4% 3% 3%
(99)
:z 5% 3%
(36)
27% 16% 5%
(43)
(90)
NOTE. Chi-squared (df = 3): NS, not significant; Abbreviation: DEP, major depressive disorder.
(38)
(48)
2:% 13% 7%
*P < .05; W < .Ol; SP < ,005.
(40) !Z NS (52) N’S * NS (39) * * (46) ::
525
ALCOHOL AND DEPRESSION
the female probands (x2 = 13.4, df = 6, P < .OS), particularly among male relatives of the female probands (x’ = 14.8, df = 6, P < .02). These associations are consistent with Coryell’s suggested relationship between proband alcoholism and secondary depression in relatives. These associations for primary versus secondary depression were not evident among the female relatives; instead, the females showed a clear association between primary depression in relatives and depression with or without alcoholism in the probands. We then examined these associations using logistic regression to adjust for relatives’ age, sex, and interview status. For primary depression, interview status, proband depression, and the interaction of proband sex with proband depression were statistically significant. For secondary depression, only interview status, but not depression, was significant. Thus, addicts’ depression was associated with relatives’ primary depression and not with relatives’ secondary depression, although addicts’ alcoholism may be associated with relatives’ secondary depression in females. As shown in Table 4, alcoholism rates are highest in relatives of depressed alcoholic probands (33%) and this association is stronger for females. Only the male relatives of the male probands fail to conform to this pattern, and this stratum (line 2) fail to show overall statistical significance. Female relatives most strongly showed the associations that Coryell’s review suggests between alcoholism in relatives and proband depression. The highest rate of alcoholism occurred in the female relatives of probands with both alcoholism and depressive disorders (29%) and the rates of alcoholism in female relatives of probands with depression only (16%) were comparable to the rates in female relatives of probands with alcoholism only (13%) (x’ = 18.3, df = 3, P < .OOOl).As shown in line 4 of Table 4, the female relatives of the male probands showed this linear trend association quite clearly with alcoholism rates rising in the female relatives from 5% (proband neither depressed nor alcoholic) to 16% (proband depressed only) to 22% (proband alcoholic only) to 27% (proband depressed plus alcoholic) (x2 = 8.3, df = 1, P < .Ol, for linear trend). Similar findings resulted when the seven probands with primary depression were excluded. Using logistic regression to adjust for relatives’ age, sex and interview status, the Table 4. Rates per 100 of Alcoholism in the First-Degree Relatives of Opioid Addicts by Relatives’ and Probands’ Gender (n = 877) Relatives of Alcoholic Probands
Gender Relatives
Probands
All Male Male Female Female
All Male Female Male Female
Proband Depressed
Relatives of Nonalcoholic Probands
Proband Nondepressed
Proband Depressed
Proband Nondepressed
% ALC
(n)
%ALC
(n)
%ALC
(n)
%ALC
(n)
X*
33% 32% 42% 27% 30%
(350) (87) (90) (74) (99)
25% 40% 26% 22% 3%
(175) (55) (38) (46) (36)
17% 22% 15% 16% 16%
(175) (46) (48) (38) (43)
21% 20% 40% 5% 13%
(177) (40) (52) (39) (46)
* NS t * t
NOTE. Chi-squared (df = 3): NS, not significant; *P < .05; tP < .Ol; SP < .OOOl. Abbreviation: ALC, alcoholism.
526
KOSTEN, KOSTEN, AND ROUNSAVILLE
association between relatives’ alcoholism and proband alcoholism (x” = 6.8, df = 1, P < .Ol), relatives’ sex (x2 = 14.8, df = 1, P < .OOOl),and interview status (x2 = 26.2, df = 1, P < .OOOl)were statistically significant, and the residual term in the unsaturated (main effects only) model was not statistically significant (x2 = 60, d’= 68, P < 0.7). When we examined separately the female relatives using logistic regression, relatives’ alcoholism was significantly associated with proband depression (x2 = 3.9, df = 1, P < .05), which is consistent with Coryell’s conclusions that secondary depression in relatives is associated with alcoholism in the proband. DISCUSSION
Several gender-related associations between alcoholism and depression in opioid addicts were examined in view of Coryell’s’ conclusions about primary and secondary depression in alcoholics. Previous studies among alcoholics have suggested that although alcoholism is not associated with primary depression, alcoholism might be associated with secondary depression in the alcoholics’ relatives.‘,’ Our study found that probands’ alcoholism was associated with relatives’ alcoholism and that probands’ depression was associated with relatives’ primary depression, but not secondary depression. An association between alcoholism in probands and primary depression in their relatives was not supported, but an association was suggested between probands’ alcoholism and relatives’ secondary depression. This secondary depression association was stronger in females than in males and may be related more to psychosocial than to genetic factors.14-16For example, the family disruption of having an alcoholic parent may lead to later secondary depressive disorders in women substance abusers. While these findings might be limited by an opioid addict sample, the high rates of alcoholism and depression in both the probands and their relatives provided the advantage of a sufficient sample size for detailed analyses by gender groups. The rates of alcoholism among both the opioid addict probands and their first-degree relatives were high in this sample, with 60% of the probands being alcoholic and 26% of all relatives being alcoholic. The rate of depression among the probands had been selected by the study design to be high (62%) and the rate in the relatives was moderately high (16%) with adequate rates of both primary and secondary depression. Thus, a reasonable test of familial association between alcoholism and both primary and secondary depression could be made. Our data might support some aspects of the “depressive spectrum” hypothesis of Winokur,17X18but the data are more consistent with other studies showing independent transmission of primary depression and alcoholism in samples of alcoholic or depressed patients.5.19 In extensive reanalyses of Winokur’s and other data, Cloninger et al.’ also examined early onset depression and alcoholism as potentially associated and found that these two disorders are unlikely to be alternative expressions of the same underlying familial predisposition. Schuckit’s’ recent review concluded that the available adoption studies of alcoholism and depression do not support a close genetic relationship between primary depression and alcoholism. Our data suggesting an association between secondary depression and alcoholism were not strong, but merit further consideration, particularly in samples with adequate representation of females.
ALCOHOL
527
AND DEPRESSION
REFERENCES 1. Hesselbrock MN, Meyer RE, Keener JJ: Psychopathology in hospitalized alcoholics. Arch Gen Psychiatry 42:1050-1055, 1985 2. Rounsaville BJ, Weissman MM, Kleber HD, et al: Heterogeneity of psychiatric diagnosis in treated opiate addicts. Arch Gen Psychiatry 39:161-166, 1982 3. Rounsaville BJ, Kosten TR, Weissman MM, et al: Psychiatric disorders in the relatives of probands with opioid addiction. Arch Gen Psychiatry 48:33-43,199l 4. Kosten TR, Rounsaville BJ, Kleber HD: Parental alcoholism in opiate addicts. J Nerv Ment Dis 173:461-469, 1985 5. Cloninger CR, Reich T, Wetzel R: Alcoholism and affective disorders: Familial associations and genetic models, in Goodwin DW, Erikson CK (eds): Alcoholism and Affective Disorders: Clinical, Genetic and Biochemical Studies. New York, NY, SP Medical and Scientific, 1979, pp 57-86 6. Cadoret RJ: Depression and alcoholism, in Meyer RE, Babor TF, Glueck BC, et al (eds): Evaluation of the Alcoholic: Implications for Research, Theory and Treatment. Research Monograph 5, Washington, DC, National Institute on Alcohol Abuse and Alcoholism, 1980, pp 59-68 7. Schukit M: Genetic and clinical implications of alcoholism and affective disorder. Am J Psychiatry 143:140-147.1986 8. Coryell W: A family study perspective on the co-existence of alcoholism and depression. Presented at NIMH Workshop on Causal Priority of Psychopathology and Substance Abuse. Rockville, MD, October 26, 1990 9. Endicott J, Spitzer RL: A diagnostic interview: The Schedule for Atfective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837-844, 1978 10. Leckman JF, Sholomskas D, Thompson WD, et al: Best estimate of lifetime psychiatric diagnosis. Arch Gen Psychiatry 39:879-883, 1982 11. Kosten TR, Rounsaville BJ, Kosten TA, et al: Gender differences in the specificity of alcoholism transmission among the relatives of opioid addicts. (submitted) 12. Andreasen NC, Endicott J, Spitzer RL, et al: The family history method using diagnostic criteria. Arch Gen Psychiatry 34:1229-1235, 1977 13. Fienberg SE: The Analysis of Cross-Classified Categorical Data (ed 2). Cambridge, MA, MIT Press, 1980 14. Huba GJ, Wingard JA, Bentler PM: Longitudinal analysis of the role of peer support, adult models, and peer subcultures in beginning adolescent substance use: An application of sehvise canonical correlation methods. Multiv Behav Res 15259-279, 1979 15. Jessor R, Jessor SL: Problem Behavior and Psychosocial Development: A Longitudinal Study of Youth. San Diego, CA, Academic, 1977 16. Kandel DB: Convergences in longitudinal surveys of drug use in normal populations, in Kandel DB (ed): Longitudinal Research on Drug Use. Washington, DC, Hemisphere, 1978, pp 3-38 17. Winokur G: Familial (genetic) subtypes of pure depressive disease. Am J Psychiatry 136:91l913,1979 18. Winokur G: Depression spectrum disease: Description and family study. Compr Psychiatry 13:3-8, 1972 19. Merikangas KR, Leckman JF, Prusoff BA, et al: Familial transmission of depression and alcoholism. Arch Gen Psychiatry 42:367-372, 1985
D
EPRESSIVE DISORDERS are common among both alcoholics and opioid addicts,‘,2 as well as among their relatives,‘~’ suggesting a familial relationship between depression and substance abuse. While the consensus of many studies, as summarized by Schuckit,’ has been that alcoholism and primary depressive disorders show independent transmission in families, a recent review by CoryelP has suggested that secondary depression is associated with alcoholism in family members. These secondary depressions are defined in terms of age of onset, and in most substance abusers the age of onset for depression is after the age of onset for the substance dependence. Since there is a large co-occurrence of depression and alcoholism in opioid addicts and their relatives, this association with secondary depression might also be examined among opioid addicts and their first-degree relatives. Coryel? has further suggested that this association may be stronger in females than in males. By comparing rates of alcoholism and of primary and secondary depression in the male and female relatives of our probands, we will examine this gender difference in associations. To facilitate this examination of gender differences, we oversampled female opioid addicts to attain equal proportions of males and females in the proband group. Since the probands have predominantly secondary, not primary, depressive disorders, statistically significant associations for the whole sample will also be examined after excluding probands with primary depression. Comparisons in rates of depression and alcoholism in relatives will be made across four proband groups: (1) depression plus alcoholism, (2) depression alone, (3) alcoholism alone, (4) neither disorder in the proband. In these comparisons, several findings would be consistent with Coryell’s assessment of the alcoholism studies on secondary depression. First, the rates of primary depression in relatives
From the Substance Abuse Treatment Unit, Connecticut Mental Health Center, Depanments of Pvchiatry and Epidemiology Yale University School of Medicine, New Haven, CT. Suppotied by grants from ADAMHA including Center Grants No. P50-DAO4060, ROI-DA03090, and ROI-DA05348 and Research Career Development Awards No. DA00089 to B.J.R. and DA00112 to T.R. K. Address reprint requests to Thomas R. Kosten, M.D., Substance Abuse Treatment Unit. 27 Sylvan Al,e, New Haven. CT 06519. Copyright 0 1991 by W B. Saunders Company 0010-440X/91 132060002$03.00/0 Comprehensive
Psychiatry,
Vol. 32, No. 6 (November/December),
1991: pp 521-527
521
522
KOSTEN, KOSTEN, AND ROUNSAVILLE
will not be associated with proband alcoholism, while secondary depression will be higher in relatives of probands with alcoholism plus depression or with alcoholism alone than in relatives of probands with depression alone. Second, this association of proband alcoholism with relatives’ secondary depression will be stronger in females than in males. Third, alcoholism rates in relatives of probands with depression, which is almost entirely secondary depression, will be increased compared with those relatives of probands without depression, and those relatives of probands with alcoholism plus depression will have the highest rates of alcoholism among the four proband groups. Fourth, this association of relatives’ alcoholism with probands’ secondary depression will be stronger in females than in males. METHOD Overall Study Design This study is a case control design in which white opioid addicts were matched on age and sex for opioid dependence with or without depression. Race was not a matching factor, as all the probands were white. The study was also a family study in which we attempted to interview directly all first-degree relatives and spouses. When direct interviews were not possible, information was determined from family history reports by relatives.
Opioid Addict Probands Adult, white, opioid-addicted probands from the Substance Abuse Treatment Unit of the Connecticut Mental Health Center were interviewed between 1983 and 1985. Opioid dependence was defined as both meeting the Research Diagnostic Criteria (RDC) for opioid dependence and having used opioids regularly for at least 2 years. To identify probands, all white, adult, nonadopted patients who were seeking treatment for opioid dependence (n = 348) were screened for psychiatric diagnosis using the Lifetime Version of the Schedule for Affective Disorders and Schizophrenia (SADS-L).“ Among those screened, 103 (30%) were excluded, because of failure to meet criteria for one of the cells, such as being a depressed female after this cell was already filled, and 42 (12%) refused to participate. The 201 (58%) study participants included a depressed group who met criteria for both opioid dependence and major depression, but did not meet criteria for bipolar illness, schizophrenia, briquet’s disorder, or unspecified functional psychosis. We required that depressive symptoms were not drug-related, as described elsewhere.‘,’
Diagnostic Assessment of Relatives The procedure for making diagnostic assessments of the first-degree relatives used the best estimate technique of Leckrnan et al.“.” For the diagnosis of alcoholism, this technique has shown excellent reliability between evaluators, and validity in comparison to direct interview diagnoses. The 201 opioid-addicted probands identified 879 first-degree relatives, including two fathers on whom no information was available, leaving 877 adult (age 18 and older) relatives. Of these, 234 were interviewed directly, 264 were not interviewed but were diagnosed on the basis of family history information from the proband and at least one additional informant, and 379 were not interviewed, and diagnosis was based on proband report only. For opioid-dependent probands and their families, two psychologists experienced with the diagnostic system made an initial best estimate diagnosis based on review of all available information. For directly interviewed relatives, the SADS-L with RDC criteria was used in an identical procedure to that used for the probands. For those relatives not directly interviewed, the family history RDC developed by Andreasen et al.” was used with structured interviews of the proband and any available relatives in order to collect data for diagnoses. In those cases in which the subject met the criteria for any psychiatric disorder, the records and interviews were reviewed independently by a second diagnostician. Any substantial disagreements between the two diagnosticians were reviewed on a case-by-case basis. The details of the best estimate procedure for the current study are described elsewhere.3
ALCOHOL
523
AND DEPRESSION
Data Analysis We used chi-square analysis to compare groups on rates of familial alcoholism, with logistic regression analysis for multiway contingency tables. In logistic regression, the dependent variable, alcoholism in the relatives of the proband, is given a logistic transformation yielding the logit or log odds ratio. The multiplicative factor by which the odds increase or decrease relative to changes in the predictor variables was then determined.” These predictor variables included relatives’ sex, age, and interview status. The design features of proband diagnostic group and sex were also included in these regression analyses in order to determine the independent association of familial alcoholism with proband alcoholism. Parameters in these logistic models were determined using maximum likelihood estimates. Interaction terms were added to test specific hypotheses, and goodness of fit was considered satisfactory, if the residual likelihood ratio chi-square was not statistically significant.
RESULTS Among the 201 opioid addict probands, 121 (60%) met RDC criteria for alcoholism some time in their lives, and 125 (62%) had been selected, because they met criteria for major depressive disorder. As shown in Table 1, the four proband groups formed by the cross tabulation of depression with alcoholism did not differ in sex, age, social class, religion, or marital status. One hundred eighteen (94%) of the probands had secondary depressions, with the mean age of onset for depression being 21 years (SD 6.0), and for substance dependence being 15 years (SD 2.7) among the 125 depressed probands. The first-degree relatives of the probands included 228 alcoholics (26%) and 139 depressives (16%). Primary depression was determined by selecting depressed relatives whose age of onset for depression preceded substance abuse or who were without alcohol or other drug abuse. Eighty-seven relatives (10% overall or 63% of depressives) had primary depression, and 50 relatives (6% overall) had secondary depressions: 18 due to alcoholism alone, 17 due to drug dependence alone, and 15 due to both disorders. As described in previous publications, both depression and alcoholism in the probands were associated with similar disorders in their first-degree relatives.“” Before examining the co-occurrence of depression and alcoholism in the probands and their relatives, we compared the demographics of the relatives in the four proband groups formed by cross-tabulating proband alcoholism with depression. These four groups did not differ significantly in age, sex, relationship to proband, percent living, or percent interviewed, as shown in Table 2. We first examined depressive disorders in the probands’ relatives, as outlined above. As shown in Table 3, rates of depression were higher in relatives of Table 1. Demographics
of Opiate Addict Probands by Major Depression and Alcoholic Versus Nonalcoholic (n = 201) Alcoholic Probands (n = 121)
Characteristic % Male (n) Age in years (SD) % Married (n) % Class l-3 % Class 4-5
Depressed (n = 84) 46% 28 29% 22% 78%
(39) (4) (24) (18) (66)
Nondepressed (n = 37) 59% (22) (3) :z% (12) 15% (5) 86% (32)
Nonalcoholic Probands (n = 80) Depressed (n = 41) 42% 30 39% 34% 66%
(17) (4) (16) (13) (28)
Nondepressed (n = 39) 44% (17) (4) :Y% (14) 30% (11) 70% (28)
KOSTEN, KOSTEN, AND ROUNSAVILLE
524
Table 2. Demographics
of First-Degree Relatives of Opiate Addicts by Major Depression and Alcoholic Versus Nonalcoholic (n = 877) Relatives of Nonalcoholic Probands (n = 352)
Relatives of Alcoholic Probands (n = 525)
Characteristic
% male (n) Age in years (SD) Relationship % Parent % Sibling % Interview
Proband Depressed (n = 350)
Proband Depressed (n = 175)
Proband Nondepressed (n = 175)
Proband Nondepressed (n = 177)
51% (178) 41 (16)
53% 42
(93) (15)
54% (94) 44 (16)
52% 41
(92) (16)
48% (167) 52% (183) 29% (100)
42% (74) 58% (101) 24% (42)
47% (82) 53% (93) 30% (53)
44% (77) 57% (100) 21% (37)
depressed probands (line l), and this association held for primary (line 2), but not for secondary (line 3), depression. When we examined this distinction between primary and secondary depression by relative and proband gender, the most informative comparison was between the relatives of probands with either depression or alcoholism alone. For example, as shown in lines 8 and 9 for male relatives of female probands, the rate for primary depression was four times higher than for secondary depression in the relatives of probands with depression alone (17% v 4%), while the relatives of probands with alcoholism alone had the converse relationship with higher secondary than primary depression rates (0 v 8%). This same pattern can be seen in the male relatives of the male probands. This pattern is statistically significant for primary versus secondary depression in Table 3. Rates per 100 of Primary and Secondary Major Depressive Disorder in the First-Degree Relatives of Opioid Addicts by Relatives’ and Probands’ Gender (n = 877) Relatives of Alcoholic Probands
Gender Relatives
Probands
All
All
Male
Male
Male
Female
Female
Male
Female
Female
Relatives Depressed ALL Primary Second ALL Primary Second ALL Primary Second ALL Primary Second ALL Primary Second
Relatives of Nonalcoholic Probands
Proband Nondepressed
Proband Depressed
Proband Depressed
Proband Nondepressed
% DEP
(n)
% DEP
(n)
% DEP
(n)
% DEP
(n)
x2
19% 13% 6% 13% 8% 5% 13% 5% 8% 24% 20% 4% 26% 18% 8%
(35)
13% 6%
(175)
(175)
11% 6%
(177)
* t
(87)
1::; 5% 13% 8% 0
(55)
17% 13% 4% 4% 4% 0 21% 17%
(46)
(74)
IZ 11%
(46)
2::; 13%
(38)
IZZ 5% 10% 6% 2% 4% 3% 3%
(99)
:z 5% 3%
(36)
27% 16% 5%
(43)
(90)
NOTE. Chi-squared (df = 3): NS, not significant; Abbreviation: DEP, major depressive disorder.
(38)
(48)
2:% 13% 7%
*P < .05; W < .Ol; SP < ,005.
(40) !Z NS (52) N’S * NS (39) * * (46) ::
525
ALCOHOL AND DEPRESSION
the female probands (x2 = 13.4, df = 6, P < .OS), particularly among male relatives of the female probands (x’ = 14.8, df = 6, P < .02). These associations are consistent with Coryell’s suggested relationship between proband alcoholism and secondary depression in relatives. These associations for primary versus secondary depression were not evident among the female relatives; instead, the females showed a clear association between primary depression in relatives and depression with or without alcoholism in the probands. We then examined these associations using logistic regression to adjust for relatives’ age, sex, and interview status. For primary depression, interview status, proband depression, and the interaction of proband sex with proband depression were statistically significant. For secondary depression, only interview status, but not depression, was significant. Thus, addicts’ depression was associated with relatives’ primary depression and not with relatives’ secondary depression, although addicts’ alcoholism may be associated with relatives’ secondary depression in females. As shown in Table 4, alcoholism rates are highest in relatives of depressed alcoholic probands (33%) and this association is stronger for females. Only the male relatives of the male probands fail to conform to this pattern, and this stratum (line 2) fail to show overall statistical significance. Female relatives most strongly showed the associations that Coryell’s review suggests between alcoholism in relatives and proband depression. The highest rate of alcoholism occurred in the female relatives of probands with both alcoholism and depressive disorders (29%) and the rates of alcoholism in female relatives of probands with depression only (16%) were comparable to the rates in female relatives of probands with alcoholism only (13%) (x’ = 18.3, df = 3, P < .OOOl).As shown in line 4 of Table 4, the female relatives of the male probands showed this linear trend association quite clearly with alcoholism rates rising in the female relatives from 5% (proband neither depressed nor alcoholic) to 16% (proband depressed only) to 22% (proband alcoholic only) to 27% (proband depressed plus alcoholic) (x2 = 8.3, df = 1, P < .Ol, for linear trend). Similar findings resulted when the seven probands with primary depression were excluded. Using logistic regression to adjust for relatives’ age, sex and interview status, the Table 4. Rates per 100 of Alcoholism in the First-Degree Relatives of Opioid Addicts by Relatives’ and Probands’ Gender (n = 877) Relatives of Alcoholic Probands
Gender Relatives
Probands
All Male Male Female Female
All Male Female Male Female
Proband Depressed
Relatives of Nonalcoholic Probands
Proband Nondepressed
Proband Depressed
Proband Nondepressed
% ALC
(n)
%ALC
(n)
%ALC
(n)
%ALC
(n)
X*
33% 32% 42% 27% 30%
(350) (87) (90) (74) (99)
25% 40% 26% 22% 3%
(175) (55) (38) (46) (36)
17% 22% 15% 16% 16%
(175) (46) (48) (38) (43)
21% 20% 40% 5% 13%
(177) (40) (52) (39) (46)
* NS t * t
NOTE. Chi-squared (df = 3): NS, not significant; *P < .05; tP < .Ol; SP < .OOOl. Abbreviation: ALC, alcoholism.
526
KOSTEN, KOSTEN, AND ROUNSAVILLE
association between relatives’ alcoholism and proband alcoholism (x” = 6.8, df = 1, P < .Ol), relatives’ sex (x2 = 14.8, df = 1, P < .OOOl),and interview status (x2 = 26.2, df = 1, P < .OOOl)were statistically significant, and the residual term in the unsaturated (main effects only) model was not statistically significant (x2 = 60, d’= 68, P < 0.7). When we examined separately the female relatives using logistic regression, relatives’ alcoholism was significantly associated with proband depression (x2 = 3.9, df = 1, P < .05), which is consistent with Coryell’s conclusions that secondary depression in relatives is associated with alcoholism in the proband. DISCUSSION
Several gender-related associations between alcoholism and depression in opioid addicts were examined in view of Coryell’s’ conclusions about primary and secondary depression in alcoholics. Previous studies among alcoholics have suggested that although alcoholism is not associated with primary depression, alcoholism might be associated with secondary depression in the alcoholics’ relatives.‘,’ Our study found that probands’ alcoholism was associated with relatives’ alcoholism and that probands’ depression was associated with relatives’ primary depression, but not secondary depression. An association between alcoholism in probands and primary depression in their relatives was not supported, but an association was suggested between probands’ alcoholism and relatives’ secondary depression. This secondary depression association was stronger in females than in males and may be related more to psychosocial than to genetic factors.14-16For example, the family disruption of having an alcoholic parent may lead to later secondary depressive disorders in women substance abusers. While these findings might be limited by an opioid addict sample, the high rates of alcoholism and depression in both the probands and their relatives provided the advantage of a sufficient sample size for detailed analyses by gender groups. The rates of alcoholism among both the opioid addict probands and their first-degree relatives were high in this sample, with 60% of the probands being alcoholic and 26% of all relatives being alcoholic. The rate of depression among the probands had been selected by the study design to be high (62%) and the rate in the relatives was moderately high (16%) with adequate rates of both primary and secondary depression. Thus, a reasonable test of familial association between alcoholism and both primary and secondary depression could be made. Our data might support some aspects of the “depressive spectrum” hypothesis of Winokur,17X18but the data are more consistent with other studies showing independent transmission of primary depression and alcoholism in samples of alcoholic or depressed patients.5.19 In extensive reanalyses of Winokur’s and other data, Cloninger et al.’ also examined early onset depression and alcoholism as potentially associated and found that these two disorders are unlikely to be alternative expressions of the same underlying familial predisposition. Schuckit’s’ recent review concluded that the available adoption studies of alcoholism and depression do not support a close genetic relationship between primary depression and alcoholism. Our data suggesting an association between secondary depression and alcoholism were not strong, but merit further consideration, particularly in samples with adequate representation of females.
ALCOHOL
527
AND DEPRESSION
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