Association of Bipolar and Substance Use Disorders in Parents of Adolescents With Bipolar Disorder

Association of Bipolar and Substance Use Disorders in Parents of Adolescents With Bipolar Disorder Timothy E. Wilens, Joseph Biederman, Joel Adamson, Michael Monuteaux, Aude Henin, Stephanie Sgambati, Alison Santry, and Stephen V. Faraone Background: We have previously shown that juvenile bipolar disorder (BPD) is a risk for substance use disorders (SUD). Here we examine the expression of both disorders in families of youth with BPD to evaluate the familial risk mechanism. Methods: We studied 108 adolescent BPD probands with 187 parents (34 with SUD and 58 parents) and 96 control probands with 177 parents with structured interviews. We compared the prevalence of BPD and SUD with Cox proportional hazards models with time to onset of BPD or SUD as the dependent variable and proband diagnosis (Control, BPD, or BPD⫹SUD) as the independent variable. Results: The parents of the proband youth with BPD (without SUD) and BPD⫹SUD were more likely to develop BPD than the parents of control subjects [omnibus test ␹2 ⫽ 10.18, p ⫽ .006]; we found no differences between the two bipolar groups. Parents of proband youth with BPD and with BPD⫹SUD were more likely than relatives of control subjects to develop SUD [omnibus test ␹2 ⫽ 14.69, p ⬍ .001]; however, we found no differences between the parents of the two proband bipolar groups. Within the parents of proband youth with BPD⫹SUD, we found higher risk of SUD in parents with BPD than in those without BPD [␹2 ⫽ 8.39, p ⫽ .004], although the frequency of BPD was low in this group of parents. Conclusions: Bipolar disorder and SUD are prevalent in the first-degree relatives of adolescents with BPD. Adults with BPD were more likely to manifest SUD with preliminary evidence of BPD and SUD cosegregation. Key Words: Adolescents, bipolar disorder, cosegregation, familial, parents, substance abuse

R

ecent studies of adolescents and adults indicate an important relationship between bipolar disorder (BPD) and substance use disorders (SUD; including drug and alcohol abuse or dependence) (Dunner and Feinman 1995; Dunner et al. 1979; McElroy et al. 2001; Strakowski et al. 1992, 1995, 1998, 2000; Winokur et al. 1993, 1995). These data signal that childhood or early onset BPD is particularly related to a high risk for SUD (Dunner and Feinman 1995; Dunner et al. 1979; Lin et al. 2006). For example, Lin et al. (2006) described that the onset of BPD disorder before 21 years of age was associated with a higher risk for SUD. A growing body of literature also shows a strong association between SUD and BPD in adolescents (West et al. 1996; Wilens et al. 1999, 2004). We have previously shown that BPD in adolescence is a major risk factor for SUD independent of conduct disorder (Wilens et al. 1999, 2004). Although high SUD rates are reported in samples of adolescents with BPD, the mechanism of association remains unclear. Although environmental and intrapsychic issues play a role (Faraone et al. 1997; Wilens et al. 1999), the familial relationship between these two disorders in adolescent samples remains unstudied. Evaluating familial risks will allow us to better understand the youth’s intrinsic and extrinsic vulnerabilities to SUD.

From the Pediatric Psychopharmacology Unit (TEW, JB, JA, MM, AH, SS, AS), Massachusetts General Hospital; Department of Psychiatry (TEW, JB, MM), Harvard Medical School, Boston, Massachusetts; and Neuroscience & Physiology (SVF), Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, New York. Address reprint requests to Timothy Wilens, M.D., Massachusetts General Hospital, Pediatric Psychopharmacology Unit, 32 Fruit St, Yawkey Center of Outpatient Care-YAW-6A-6900, Boston, MA 02114, Tel: 617-726-1731, FAX: 617-724-3742; E-mail: [email protected]. Received August 25, 2006; revised November 21, 2006; accepted November 22, 2006.

0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.11.022

Likewise, understanding the relationship between SUD and BPD in parents will provide additional data on ultimate risks in those who have passed through the age of SUD risk. Studies indicate that genes and environment have etiologic roles in the development of alcohol and drug use disorders (Bierut et al. 1998; Cadoret 1980, 1991; Cloninger et al. 1981; Merikangas et al. 1998, 1991; Mirin et al. 1986; Pickens et al. 1991; Schuckit 1986; Tsuang et al. 1996, 1998). Similarly, BPD has a substantial genetic component (Faraone and Santangelo 1992; Strober 1992; Todd et al. 1996a, 1996b) with twin studies indicating a heritability of .6 –.8, as well as 30%– 40% of BPD youth having a first degree relative with BPD (Goodwin and Jamison 1990; Strober et al. 1988; Todd et al. 1996b). The family-study literature linking BPD and SUD has produced conflicting findings (Winokur et al. 1993). Several studies have shown a familial association between BPD and SUD (Dunner et al. 1979; Maier and Merikangas 1996; Morrison 1975; Penick et al. 1978; Raskin and Miller 1993), raising the question that the two might share genetic or other etiologic factors. Conversely, Winokur et al. (1993, 1995) found a higher than expected rate of alcoholism in BPD but noted that BPD ⫹ alcoholism was not accounted for by familial alcoholism. They also observed dissimilarities in alcohol use patterns between BPD and nonBPD groups, leading them to conclude that alcoholism in BPD is secondary to BPD (Winokur et al. 1993, 1995). Given the potential differences in the familial patterns of BPD transmission in juveniles compared with adults (Geller et al. 1994; Goldstein et al. 1997; Goodwin and Erickson 1979; Strober 1992; Wozniak et al. 1995), the familial relationship between BPD and SUD in youth warrants systematic study. As part of a controlled, family-based evaluation of the risk of SUD in adolescents with BPD, we now present data on SUD and BPD in parents of adolescent probands. We hypothesized: 1) higher rates of BPD and of SUD would be observed in the parents of probands with BPD; 2) evidence of cosegregation of BPD and SUD would be observed in the parents of probands with BPD; and 3) parents with early onset BPD BIOL PSYCHIATRY 2007;62:129 –134 © 2007 Society of Biological Psychiatry

130 BIOL PSYCHIATRY 2007;62:129 –134 would be at higher risk for SUD compared with parents with later onset BPD.

Methods and Materials Subjects The current analysis is based on our baseline assessments of our ongoing, controlled, family-based study of BPD adolescents. The detailed methods of the study are described in detail elsewhere (Wilens et al. 2004). We ascertained 108 bipolar adolescent probands and 102 non–mood-disordered control probands and their first-degree relatives. Potential subjects were excluded if they had been adopted; if their nuclear family was not available; or if they had major sensorimotor handicaps (paralysis, deafness, blindness), autism, inadequate command of the English language, or a Full Scale IQ ⬍ 70. Parents provided written informed consent for their children, and children provided written assent to participate. The study was approved by the institutional review board at Massachusetts General Hospital. As described previously (Wilens et al. 2004), a two-stage ascertainment procedure selected subjects. For BPD probands and control subjects, the first stage was a systematic phone screening. The second stage was the structured psychiatric interview (described in the following section). Only subjects who received a positive (or negative for control subjects) diagnosis at both stages were included in the sample. We eliminated any mood disorder from our ascertainment of control subjects secondary to concerns of “manic switching” from dysthymia or unipolar depression to BPD (Geller et al. 1994, 2001; Strober and Carlson 1982). Assessments All diagnostic assessments were made with DSM-IV– based structured interviews, by raters with bachelor’s degrees in psychology who had been trained and supervised by senior investigators (JB, TW). Raters were blind to the ascertainment status of the probands. Psychiatric assessments relied on the Kiddie Schedule for Affective Disorders and Schizophrenia for SchoolAged Children Epidemiologic Version (K-SADS-E) (Ambrosini 2000) and were based on independent interviews with mothers and direct interviews of probands and siblings. Subjects (probands, parents, or siblings) ages 18 and older received psychiatric diagnoses in the Structured Clinical Interview for DSM-IV (SCID; Spitzer et al. 1990) with supplemental sections from the K-SADS-E for childhood diagnoses. For every diagnosis, we gathered data regarding the ages at onset and offset of full syndromatic criteria. The SUD was diagnosed on the basis of DSM-IV criteria with K-SADS-E. Rates of disorders reported are lifetime prevalence. All cases were presented to a committee composed of board certified child psychiatrists and psychologists. Diagnoses presented for review were considered positive only if the diagnosis would be considered clinically meaningful. All cases of suspected SUD were reviewed with a child and adult psychiatrist with addiction credentials. We computed ␬ coefficients of agreement by having three experienced, board-certified child and adult psychiatrists diagnose subjects from audiotaped interviews made by the assessment staff. On the basis of 500 assessments from interviews of children and adults, the median ␬ coefficient was .98. The ␬ coefficients for individual diagnoses included: attention-deficit/ hyperactivity disorder (ADHD) (.88), conduct disorder (CD) (1.0), oppositional defiant disorder (ODD) (.90), antisocial perwww.sobp.org/journal

T.E. Wilens et al. sonality disorder (ASPD) (.80), major depression (1.0), mania (.95), and SUD (1.0). Statistical Analyses We characterized family environment with intactness (divorced/separated or intact) and the five-point HollingsheadRedlich Socioeconomic Status (SES) scale, in which higher numbers indicate lower SES. We used logistic regression for binary outcomes, Fisher’s Exact Test for hypotheses of assortative mating, linear regression for age, and ordinal logistic regression for SES. We divided probands and relatives into three groups on the basis of proband BPD and proband SUD: Control, BPD⫺SUD (no lifetime history of substance use), and BPD⫹SUD (lifetime history of substance use). We ascertained 6 control probands who endorsed SUD; we eliminated this group of probands and their 12 relatives from this analysis due to low statistical power caused by small sample size. For a second set of analyses, we grouped relatives according to proband BPD and parent BPD diagnosis into Control, BPD Parents without BPD, and BPD Parents with BPD. We calculated Kaplan-Meier failure curves to describe the time to onset of BPD or SUD; we used Cox Proportional Hazards models to compare failure curves between groups. We used Huber-White robust variance estimators to account for repeated measures within families. We considered a p value significant for demographic variables at the .1 level and significant at the .05 level elsewhere; all statistical tests are two-tailed. If an omnibus test reached significance, we tested for pairwise differences between groups with linear Wald tests. All statistical tests were performed with Stata (2005) 9.2.

Results Demographics Overall, our BPD and control probands were of similar age (Control 13.8 ⫾ 2.1 years vs. BPD 13.6 ⫾ 2.5, p ⫽ .5). Table 1 compares the demographics of parents of three groups of probands: Control, BPD⫺SUD, and BPD⫹SUD. Parents of BPD⫺SUD probands were significantly younger than parents of control subjects. We found a significant difference across the three groups in the gender of parents. All analyses comparing parents of control probands with parents of BPD probands corrected for gender. We found no differences in intactness between BPD⫺SUD, BPD⫹SUD, and control families. Families of BPD probands had significantly lower SES, and in our sample lower SES predicted SUD (logistic regression: odds ratio 1.64, Table 1. Demographics of Parents, Siblings, and Families Control n ⫽ 96

BPD ⫺ SUD BPD ⫹ SUD n ⫽ 74 n ⫽ 34

Parents n ⫽ 177 n ⫽ 129 Age, mean ⫾ SD 46.2 ⫾ 6.9 43.1 ⫾ 6.1a Gender (male), n (%) 83 (47) 55 (42)c Families n ⫽ 96 n ⫽ 74 SES, mean ⫾ SD 1.9 ⫾ 0.9 2.2 ⫾ .9b Intactness, n (%) 54 (56) 42 (57)

n ⫽ 58 44.8 ⫾ 5.7 25 (43) n ⫽ 34 2.0 ⫾ .9c 18 (53)

Omnibus Statistic

p

F ⫽ 5.9

.003

␹2 ⫽ 5.43

.07

␹2 ⫽ 12.26 .002 ␹2 ⫽ .2 .93

Pairwise tests versus Control. BPD, bipolar disorder; SUD, substance use disorder; SES, socioeconomic status. a p ⱕ .001. b p ⱕ .01. c p ⱕ .05.

BIOL PSYCHIATRY 2007;62:129 –134 131

T.E. Wilens et al. Table 2. Age and Gender in Parents Stratified by Proband and Parent BPD Diagnosis Control Parents n ⫽ 177 Age, mean ⫾ SD 46.2 ⫾ 6.9 Gender (male), n (%) 83 (47)

BPD Parents BPD Parents Without BPD With BPD Omnibus n ⫽ 159 n ⫽ 27 Statistic 44.0 ⫾ 5.6a

41.8 ⫾ 8.0a

64 (40)a

16 (57)

F ⫽ 5.5

p .005

␹2 ⫽ 8.42 .01

Pairwise tests versus Control. Abbreviations as in Table 1. a p ⱕ .01.

95% confidence interval 1.31–2.08, p ⬍ .001); all further analyses controlled for SES. Table 2 shows the age and gender of parents stratified by proband BPD status and parental BPD status. Both groups of BPD parents were significantly younger than control parents; we did not find differences in age between the two BPD parent groups. The BPD parents without BPD were significantly more likely to be male. All analyses of these groups corrected for gender. Risk of BPD and SUD in Relatives Figure 1 shows the cumulative lifetime prevalence of BPD by age of parents of adolescent probands. Parents of BPD⫺SUD and BPD⫹SUD probands were more likely to develop BPD than parents of control probands [BPD⫺SUD compared with control subjects: ␹2 ⫽ 10.2, p ⫽ .001; BPD⫹SUD compared with control subjects: ␹2 ⫽ 6.5, p ⫽ .01]. Parents of BPD⫺SUD and BPD⫹SUD probands did not differ in their risk for BPD [␹2 ⫽ .41, p ⫽ .5]. Figure 2 shows the cumulative lifetime prevalence of SUD by age of the parents of control and bipolar probands. Parents of BPD⫺SUD and BPD⫹SUD probands were more likely to develop SUD than parents of control probands [BPD⫺SUD compared with control subjects: ␹2 ⫽ 10.6, p ⫽ .001; BPD⫹SUD compared with control subjects: ␹2 ⫽ 10.4, p ⫽ .001]. We found no differences in SUD between the parents of probands with BPD⫺SUD compared with BPD⫹SUD [␹2 ⫽ .07, p ⫽ .8]. Table 3 shows rates of alcohol abuse and dependence and drug abuse

Figure 2. Age-adjusted lifetime prevalence of substance use disorder (SUD) in parents of adolescent probands stratified by proband status and proband SUD diagnosis; sample sizes given in Figure 1; omnibus test [␹2 ⫽ 14.69, p ⬍ .001]. Other abbreviations as in Figure 1.

and dependence. We found significantly higher lifetime ageadjusted risk of alcohol abuse and drug abuse in BPD⫺SUD and BPD⫹SUD parents compared with control parents; again, we found no differences between BPD⫺SUD and BPD⫹SUD. We then evaluated the development of SUD in the parents of control probands and parents of BPD probands (Figure 3). The BPD probands’ parents without BPD were more likely to endorse SUD than parents of control subjects [␹2 ⫽ 9.4, p ⫽ .002]. The BPD probands’ parents with BPD were more likely to endorse SUD than control parents [␹2 ⫽ 33.6, p ⬍ .001] or BPD probands’ parents without BPD [␹2 ⫽ 13.5, p ⬍ .001]. Table 4 shows rates of alcohol abuse and dependence and drug abuse and dependence in Control, BPD parents without BPD, and BPD parents with BPD. We found significant variance across these groups in lifetime age-adjusted risk of all four disorders; we found significantly higher lifetime age-adjusted risk of alcohol dependence, drug abuse, and drug dependence in BPD parents with BPD compared with BPD parents without BPD. We then evaluated the onset of SUD in relation to BPD onset with SUD failure curves between parents with childhood-onset BPD (⬍ 18 years; n ⫽ 13) and those with adult-onset (n ⫽ 15). Although 74% of parents with BPD developed SUD, we found no significant differences between juvenile onset BPD and adult onset BPD in the development of SUD in the parents. Similarly, although limited by small sample sizes, within 22 parents with Table 3. Prevalence of Parental SUDs Stratified by Proband BPD and SUD Diagnoses

Alcohol Abuse Alcohol Dependence Drug Abuse Drug Dependence Figure 1. Age-adjusted lifetime prevalence of bipolar disorder (BPD) in parents of adolescent probands stratified by proband status and proband substance use disorder (SUD) diagnosis; omnibus test [␹2 ⫽ 10.18, p ⫽ .006]. Control, parents of Control probands (n ⫽ 177); BPD⫺SUD, parents of probands with BPD and no SUD (n ⫽ 129); BPD⫹SUD, parents of probands with BPD and SUD (n ⫽ 58).

Control n ⫽ 177

BPD ⫺ SUD n ⫽ 129

BPD ⫹ SUD n ⫽ 58

␹2

p

46 (27) 17 (10) 35 (20) 18 (10)

57 (45)a,b 28 (22) 41 (33)a,d 21 (17)

30 (53)a,b 9 (16) 22 (38)a,d 10 (18)

8.34 4.96 9.17 1.28

.015 .084 .010 .528

All numbers shown are n (%); Cox proportional hazards models; pairwise comparisons. Abbreviations as in Table 1. a Versus Control. b p ⱕ .05. c Versus BPD ⫺ SUD. d p ⱕ .01.

www.sobp.org/journal

132 BIOL PSYCHIATRY 2007;62:129 –134

T.E. Wilens et al.

Figure 3. Age-adjusted lifetime prevalence of SUD in parents of adolescent probands stratified by proband status and parent BPD diagnosis; Control n ⫽ 177, BPD Parents without BPD n ⫽ 159, BPD Parents with BPD n ⫽ 27; omnibus test [␹2 ⫽ 34.38, p ⬍ .001]. Other abbreviations as in Figure 1.

BPD plus SUD, we found no differences in the onset precedence of BPD to SUD with respect to juvenile onset BPD (Fisher’s Exact Test: p ⫽ .6). Evidence of Cosegregation We then evaluated whether the increased rate of BPD and SUD in parents of BPD⫹SUD probands is accounted for by cosegregation of the two disorders. Cosegregation refers to the co-transmission of two disorders in families more often than expected by chance. We found that among the parents of probands with BPD⫹SUD, parents with BPD (n ⫽ 7) were more likely to endorse SUD than those parents without BPD [n ⫽ 44; ␹2 ⫽ 8.39, p ⫽ .004; Figure 4]. However, the strength of this cosegregation finding is limited by the low frequency of BPD parents in the BPD⫹SUD group. To further evaluate the hypothesis of cosegregation, we conducted a secondary analysis including cases of subthreshold BPD, thereby increasing group size by three subjects. Without controlling for SES, which further limits sample size, we found that parents with subthreshold or full BPD (n ⫽ 10) experienced significantly greater lifetime age-adjusted risk of SUD than BPD⫹SUD parents without BPD [n ⫽ 48; ␹2 ⫽ 13.9, p ⬍ .001]. Furthermore, our conclusions were identical when we included the effects of SES [BPD n(%SUD) ⫽ 9(100%), no BPD n ⫽ 25(58%); ␹2 ⫽ 11.7, p ⬍ .001]. All results except the Table 4. Prevalence of Parental SUDs Stratified by Proband BPD and Parent SUD Diagnoses Control BPD Parents BPD Parents Parents Without BPD With BPD n ⫽ 177 n ⫽ 159 n ⫽ 27 Alcohol Abuse Alcohol Dependence Drug Abuse Drug Dependence

46 (27) 17 (10) 35 (20) 18 (10)

a,b

70 (45) 23 (15) 47 (30)a,b 18 (12)

␹2

p

a,b

17 (61) 9.24 .01 14 (56)a,c,d 29.62 ⬍.001 16 (59)a,c,d,e 20.31 ⬍.001 13 (50)a,c,d 15.56 ⬍.001

All numbers shown are n (%); Cox proportional hazards models; pairwise comparisons. Abbreviations as in Table 1. a Versus Control Parents. b p ⱕ .05. c Versus BPD Parents without BPD. d p ⱕ .001. e p ⱕ .01.

www.sobp.org/journal

Figure 4. Age-adjusted lifetime prevalence of SUD in parents of BPD⫹SUD adolescent probands stratified by parent BPD diagnosis; BPD n ⫽ 7, no BPD n ⫽ 44; [␹2 ⫽ 8.39, p ⫽ .004]. Other abbreviations as in Figure 1.

cosegregation of BPD and SUD maintained significance when we controlled for conduct and antisocial personality disorder. We also tested whether assortative mating accounts for the increased rate of BPD and SUD in parents of BPD⫹SUD probands. We found positive preference of mothers with SUD for mating with fathers with BPD in our entire sample of parents of BPD probands (Fisher’s Exact Test p ⫽ .01); however, when we restricted the sample to parents in the BPD⫹SUD group, we found no difference in the rate of SUD in the mates of mothers with BPD (100%) compared with the mates of mothers without BPD (87%; Fisher Exact Test p ⫽ 1.0; n ⫽ 25 complete pairs of parents of BPD⫹SUD probands). Likewise, the rates of SUD in mates of fathers who did have BPD (42%) did not differ from the rate of SUD in mates of fathers who did not have BPD (60%; Fisher’s Exact Test p ⫽ .5). Assortative mating cannot explain the comorbidity of BPD and SUD in parents of BPD⫹SUD probands.

Discussion Our findings from a controlled family-study of adolescents with BPD support our hypothesis of higher rates of BPD and of SUD in the parents of youth with BPD—maintained when controlling for conduct and antisocial disorders. We also found some evidence of cosegregation of BPD and SUD in the parents of youth with BPD. We failed to demonstrate that parents with childhood-onset BPD were at higher risk for SUD compared with those with later onset BPD. The aggregate data derived from the parents of our probands highlight that BPD and SUD are familial and probably cosegregate. Our findings of elevated rates of BPD and of SUD in family members of BPD individuals are similar to those of other reports in adults (Dunner et al. 1979; Maier and Merikangas 1996; Morrison 1975; Penick et al. 1978; Raskin and Miller 1993). Morrison (1975) found significantly more alcoholism in the relatives of the adult patients with BPD and alcoholism, speculating that BPD and alcoholism were independently transmitted. Our finding of a significant increase in SUD in parents of adolescents with BPD is similar to that of Todd et al. (1996a), who also reported a significantly higher prevalence of alcoholism among relatives of probands with BPD (Todd et al. 1996a). In the current study, our findings were maintained even controlling for conduct and antisocial disorders—independent risk factors for

T.E. Wilens et al. SUD—further underscoring the link between BPD and SUD in both pediatric and adult samples. We found some evidence in parents of cosegregation of BPD plus SUD: SUD was predicted by the presence or absence of BPD in the parents of our BPD⫹SUD probands—and was not accounted for by assortative mating. Our finding of a link between BPD and SUD is similar to the findings of Dunner et al. (1979), who showed that the morbid risk for any affective disorder was higher in the relatives of BPD⫹SUD compared with BPD only. Our findings of cosegregation are somewhat dissimilar to those of Winokur et al. (1993, 1995), who found a higher than expected rate of alcoholism in BPD but noted that BPD ⫹ alcoholism was not accounted for by familial alcoholism. Differences might be in the potential confound of disruptive comorbidity in Winokur et al’s sample or the age groups of the sample. Adults with BPD had higher risk for SUD compared with adults without BPD, confirming again the increased risk across the lifespan of SUD in BPD (Lin et al. 2006; McElroy et al. 2001). Furthermore, parents with BPD manifest more abuse or dependence with both alcohol and drugs relative to adults without BPD with either a drug or alcohol use disorder. Our findings of a higher risk of SUD and more pernicious SUD in adults with BPD are consistent with a growing literature (Lin et al. 2006; McElroy et al. 2001; Strakowski et al. 1995; Winokur et al. 1993). For instance, Strakowski et al. (2000) reported that the duration of alcohol and marijuana use was related to the duration of depression and mania, respectively, in a study of new onset adult BPD. These data highlight the complex relationship between BPD and SUD that onsets in adolescence (Wilens et al. 1999, 2004) and extends into adulthood (Strakowski et al. 2000). Clinicians need to be mindful that BPD at any age increases greatly the risk for SUD. Our results provide some insights into the mechanisms that might account for the comorbidity between BPD and SUDs. Our finding of cosegregation shows that comorbidity cannot be simply accounted for by referral bias or any other source of statistical artifacts. Our analyses of age at onset found that neither SUD nor BPD systematically onset before the other disorder. This suggests that neither disorder is routinely secondary to the other disorder. We found a high rate of SUD among parents of probands with BPD, regardless of proband SUD diagnosis; this finding might indicate that the two disorders share transmissible familial risk factors. For example, this transmission pattern would occur if genes that increase risk for BPD also increase risk for SUD; it would also occur if the environment created by a substanceabusing parent increased the risk for BPD in their child or if the difficulties of raising a BPD child trigger parental SUD. Our finding of a lack of consistent SUD relative to BPD partially supports the notion of secondary SUD in BPD in some adults (Strakowski et al. 1998; Winokur et al. 1995) and/or of the temporal onset of shared risk factors for both SUD and BPD. For instance, Strakowski et al. (1998) have noted a pattern by which the course of BPD is related to the course of SUD. Winokur et al. (1993, 1995) observed differences in alcohol use patterns between BPD and nonBPD suggestive of alcohol use as a result of the individual’s BPD. In the current sample, BPD was associated with increases in SUD, suggesting an effect or familial association of the BPD on the SUD. Our findings must be interpreted with some methodological limitations. The sample was primarily Caucasian and might not generalize to other ethnicities. Similarly, because our sample was drawn largely from advertisements, it might not generalize to the

BIOL PSYCHIATRY 2007;62:129 –134 133 population. The results reported are from adults and therefore are retrospective. The SUD was determined by structured interview and not by objective urine toxicologies, although recently reported data highlights the usefulness of structured psychiatric interviews for capturing current and lifetime SUD (Gignac et al. 2005). Probands in our study were not through the full risk of SUD, probably producing an under-representation of the full SUD risk. The lack of significant differences between our two groupings of parents of BPD probands might indicate censoring of SUD diagnoses in the BPD⫺SUD probands. Despite our significant finding of cosegregation, the frequency of parents of BPD⫹SUD probands showing BPD was small. Despite these limitations, our findings indicate that higher rates of both BPD and of SUD are found in the parents of probands with BPD. Likewise, parents with BPD were more likely to develop SUD than parents without BPD. The relationship of BPD and SUD in the adult parents, similar to findings in adolescents with BPD, is not accounted for by conduct or antisocial disorders. These data, derived from parents of our probands, highlight that BPD and SUD are familial and satisfy criteria for cosegregation. This study was supported by NIH RO1 DA12945 (TW), U10 DA15831 (TW) and K24 DA016264 (TW). Dr. Timothy Wilens receives grant support from the following sources: Abbott Laboratories, Ortho-McNeil, Eli Lilly and Company, National Institute on Drug Abuse (NIDA), Neurosearch, and Shire Laboratories Inc. Dr. Timothy Wilens is a speaker for the following speaker’s bureaus: Ortho-McNeil, Novartis Pharmaceuticals, and Shire Laboratories Inc. Dr. Timothy Wilens is a consultant for: Abbott Laboratories, Ortho-McNeil, Glaxo-SmithKline, Eli Lilly and Company, National Institute on Drug Abuse (NIDA), Novartis, Pfizer, Shire Laboratories Inc. Dr. Joseph Biederman receives/d research support from, is/has been a speaker for, or is/has been on the advisory board for the following pharmaceutical companies: Shire, Eli Lilly, Pfizer, McNeil, Abbott, Bristol-Myers-Squibb, New River Pharmaceuticals, Cephalon, Janssen, Novartis, UCB Pharma, Astra-Zeneca, Forest Laboratories, Glaxo-SmithKline, Neurosearch, Stanley Medical Institute, Inc, Lilly Foundation, Prechter Foundation, National Institute of Health (NIH), National Institute of Mental Health (NIMH), National Institute of Child Health and Development (NICHD), and National Institute on Drug Abuse (NIDA). Dr. Stephen Faraone receives/d research support from, is/has been a speaker for, or is/has been on the advisory board for the following companies: Eli Lilly & Company. McNeil Consumer & Specialty Pharmaceuticals, Shire US Inc., Noven Pharmaceuticals, Cephalon, National Institute of Mental Health (NIMH), National Institute of Child Health and Human Development (NICHHD), and National Institute of Neurological Disorders and Stroke (NINDS). Joel Adamson, Michael Monuteaux, Aude Henin, Stephanie Sgambati, and Alison Santry do not have any financial interests to disclose. Ambrosini PJ (2000): Historical development and present status of the schedule for affective disorders and schizophrenia for school-age children (K-SADS). J Am Acad Child Adolesc Psychiatry 39:49 –58. Bierut L, Dinwiddie S, Begleiter H, Crowe R, Hesselbrock V, Numberger J, et al. (1998): Familial transmission of substance dependence: Alcohol, marijuana, cocaine, and habitual smoking. Arch Gen Psychiatry 55:982–988. Cadoret RJ (1991): Genetic and environmental factors in initiation of drug use and the transition to abuse. In: Glantz M, Pickens R, editors. Vulnerability to Drug Abuse. Washington, DC: American Psychological Press, 99 – 114.

www.sobp.org/journal

134 BIOL PSYCHIATRY 2007;62:129 –134 Cadoret RJ, Cain CA, Grove WM (1980): Development of alcoholism in adoptees raised apart from alcoholic biologic relatives. Arch Gen Psychiatry 37:561–563. Cloninger CR, Bohman M, Sigvardsson S (1981): Inheritance of alcohol abuse: Cross-fostering analysis of adopted men. Arch Gen Psychiatry 38:861– 868. Dunner D, Hensel B, Fieve R (1979): Bipolar illness: Factors in drinking behavior. Am J Psychiatry 136:583–585. Dunner DL, Feinman J (1995): The effect of substance abuse on the course of bipolar disorder, 34th Annual Meeting of the American College of Neuropsychopharmacology. San Juan, Puerto Rico: American College of Neuropsychopharmacology, 171. Faraone SV, Biederman J, Mennin D, Wozniak J, Spencer T (1997): Attentiondeficit hyperactivity disorder with bipolar disorder: A familial subtype? J Am Acad Child Adolesc Psychiatry 36:1378 –1387; discussion 1387–1390. Faraone SV, Santangelo S (1992): Methods in Genetic Epidemiology. In: Fava M, Rosenbaum JF, editors. Research Designs and Methods in Psychiatry. Amsterdam, The Netherlands: Elsevier, 93–118. Geller B, Fox L, Clark K (1994): Rate and predictors of prepubertal bipolarity during follow-up of 6- to 12-year-old depressed children. J Am Acad Child Adolesc Psychiatry 33:461– 468. Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL (2001): Adult psychosocial outcome of prepubertal major depressive disorder. J Am Acad Child Adolesc Psychiatry 40:673– 677. Gignac M, Wilens TE, Biederman J, Kwon A, Mick E, Swezey A (2005): Assessing cannabis use in adolescents and young adults: What do urine screen and parental report tell you? J Child Adolesc Psychopharmacol 15:742– 750. Goldstein RB, Wickramaratne PJ, Horwath E, Weissman MM (1997): Familial Aggregation and phenomenology of ’early’-onset (at or before age 20 years) panic disorder. Arch Gen Psychiatry 54:271–278. Goodwin DW, Erickson CK (1979): Alcoholism and Affective Disorders: Clinical, Genetic, and Biochemical Studies. New York: Spectrum Publications, 298. Goodwin F, Jamison K (1990): Manic-Depressive Illness. New York: Oxford University Press. Lin PI, McInnis MG, Potash JB, Willour V, MacKinnon DF, DePaulo JR, et al. (2006): Clinical correlates and familial aggregation of age at onset in bipolar disorder. Am J Psychiatry 163:240 –246. Maier W, Merikangas K (1996): Co-occurence and cotransmissions of affective disorders and alcoholism in families. Br J Psychiatry 168:93–100. McElroy S, Altshuler L, Suppes T, Keck PE, Frye MA, Denicoff KD, et al. (2001): Axis I Psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry 158:420 – 426. Merikangas K, Stolar M, Stevens D, Goulet J, Preisig M, Fenton B, et al. (1998): Familial transmission of substance use disorders. Arch Gen Psychiatry 55:973–979. Merikangas KR, Rounsaville BJ, Prusoff BA (1991): Familial factors in vulnerability to substance abuse. In: Glantz M, Pickens R, editors. Vulnerability to Drug Abuse. Washington, DC: American Psychological Press, 75–97. Mirin SM, Weiss RD, Michael J (1986): Family pedigree of psychopathology in substance abusers. In: Meyer R, editor. Psychopathology and Addictive Disorders. New York: Guilford Press, 57–77. Morrison J (1975): The family histories of manic-depressive patients with and without alcoholism. J Nerv Ment Dis 160:227–229. Penick E, Reed MR, Crawley PA (1978): Differentiation of alcoholics by family history. J Stud Alcohol 39:1944 –1948. Pickens RW, Svikis DS, McGue M, Lykken DT, Heston LL, Clayton PJ (1991): Heterogeneity in the inheritance of alcoholism. Arch Gen Psychiatry 48: 19 –28. Raskin VD, Miller NS (1993): The epidemiology of the comorbidity of psychiatric and addictive disorder: A critical review. In: Miller NS, Stimmel B,

www.sobp.org/journal

T.E. Wilens et al. editors. Comorbidity of Addictive and Psychiatric Disorders. New York: The Haworth Medical Press, 45–58. Schuckit MA (1986): Genetic and clinical implications of alcoholism and affective disorder. Am J Psychiatry 143:140 –147. Spitzer RL, Williams JB, Gibbon M, First MB (1990): Structured Clinical Interview for DSM-III-R: Non-Patient Edition (SCID-NP, Version 1.0). Washington, DC: American Psychiatric Press. Stata Corporation (2005): Stata User’s Guide: Release 9. College Station, Texas: Stata. Strakowski S, McElroy S, Keck P Jr., West S (1995): The effects of antecedent substance abuse on the development of first-episode psychotic mania. J Psychiatr Res 30:59 – 68. Strakowski S, Sax K, McElroy S, Keck P, Hawkins J, West S (1998): Course of psychiatric and substance abuse syndromes co-occurring with bipolar disorder after a first psychiatric hospitalization. J Clin Psychiatry 59:465– 471. Strakowski S, Tohen M, Stoll A, Faedda G, Goodwin D (1992): Comorbidity in mania at first hospitalization. Am J Psychiatry 149:554 –556. Strakowski SM, DelBello MP, Fleck DE, Arndt S (2000): The impact of substance abuse on the course of bipolar disorder. Biol Psychiatry 48:477– 485. Strober M (1992): Relevance of early age-of-onset in genetic studies of bipolar affective disorder. J Am Acad Child Adolesc Psychiatry 31:606 – 610. Strober M, Carlson G (1982): Predictors of bipolar illness in adolescents with major depression: A follow-up investigation. Adolesc Psychiatry 10:299 – 319. Strober M, Morrell W, Burroughs J, Lampert C, Danforth H, Freeman R (1988): A family study of bipolar I disorder in adolescence: Early onset of symptoms linked to increased familial loading and lithium resistance. J Affect Disord 15:255–268. Todd R, Geller B, Neuman R, Fox L, Hickok J (1996a): Increased prevalence of alcoholism in relatives of depressed and bipolar children. J Am Acad Child Adolesc Psychiatry 35:716 –724. Todd RD, Reich W, Petti TA, Joshi P, DePaulo R, Nurnberger J, et al. (1996b): Psychiatric diagnoses in the child and adolescent members of extended families identified through adult bipolar affective disorder probands. J Am Acad Child Adolesc Psychiatry 35:664 – 671. Tsuang M, Lyons M, Meyer J, Doyle T, Eisen S, Goldberg J, et al. (1998): Co-occurence of abuse of different drugs in men: the role of drugspecific and shared vulnerabilities. Arch Gen Psychiatry 55:967–972. Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N, et al. (1996): Genetic influences on DSM-III-R drug abuse and dependence: A study of 3,372 twin pairs. Am J Med Genet 67:473– 477. West SA, Strakowski SM, Sax KW, McElroy SL, Keck PE, McConville BJ (1996): Phenomenology and comorbidity of adolescents hospitalized for the treatment of acute mania. Biol Psychiatry 39:458 – 460. Wilens T, Biederman J, Kwon A, Ditterline J, Forkner P, Chase R, et al. (2004): Risk for substance use disorders in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 43:1380 –1386. Wilens TE, Biederman J, Millstein R, Wozniak J, Hahesy A, Spencer TJ (1999): Risk for substance use disorders in youth with child- and adolescentonset bipolar disorder. J Am Acad Child Adolesc Psychiatry 38:680 – 685. Winokur G, Cook B, Liskow B, Fowler R (1993): Alcoholism in manic depressive (bipolar) patients. J Stud Alcohol 54:574 –576. Winokur G, Coryell W, Akiskal HS, Maser JD, Keller MB, Endicott J, et al. (1995): Alcoholism in manic-depressive (bipolar) illness: Familial illness, course of illness, and the primary-secondary distinction. Am J Psychiatry 152: 365–372. Wozniak J, Biederman J, Mundy E, Mennin D, Faraone SV (1995): A pilot family study of childhood-onset mania. J Am Acad Child Adolesc Psychiatry 34:1577–1583.