The co-occurrence of attention deficit hyperactivity

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1 Article Fmilil Risk Anlyses of Attention Deficit Hyperctivity Disorder nd Substnce Use Disorders Joseph Biedermn, M.D. Crter R. Petty, M.A. Timothy E. Wilens, M.D. Mri G. Frire, B.A. Citlin A. Purcell, B.A. Eric Mick, Sc.D. Michel C. Monuteux, Sc.D. Stephen V. Frone, Ph.D. Objective: A robust nd bidirectionl comorbidity between ttention deficit hyperctivity disorder (ADHD) nd psychoctive substnce use disorder (lcohol or drug buse or dependence) hs been consistently reported in the extnt literture. Method: First-degree reltives from lrge group of peditriclly nd psychitriclly referred boys with (112 probnds, 385 reltives) nd without (105 probnds, 358 reltives) ADHD were comprehensively ssessed by blind rters with structured dignostic interviews. Fmilil risk nlysis exmined the risks in first-degree reltives for ADHD, psychoctive substnce use disorder, lcohol dependence, nd drug dependence fter strtifying probnds by the presence nd bsence of these disorders. Results: ADHD in the probnd ws consistently ssocited with significnt risk for ADHD in reltives. Drug dependence in probnds incresed the risk for drug dependence in reltives irrespective of ADHD sttus, wheres lcohol dependence in reltives ws predicted only by ADHD probnds with comorbid lcohol dependence. In ddition, ADHD in the probnd predicted drug dependence in reltives, nd drug dependence in comprison probnds incresed the risk for ADHD in reltives. Both lcohol dependence nd drug dependence bred true in fmilies without evidence for common risk between these disorders. Conclusions: Ptterns of fmilil risk nlysis suggest tht the ssocition between ADHD nd drug dependence is most consistent with the hypothesis of vrible expressivity of common risk between these disorders, wheres the ssocition between ADHD nd lcohol dependence is most consistent with the hypothesis of independent trnsmission of these disorders. Findings lso suggest specificity for the trnsmission of lcohol nd drug dependence. (Am J Psychitry 2008; 165: ) The co-occurrence of ttention deficit hyperctivity disorder (ADHD) nd psychoctive substnce use disorder (lcohol or drug buse or dependence) hs been reported in vriety of clinicl nd reserch settings (1 3). Followup studies hve documented higher thn expected risk for psychoctive substnce use disorder in dults who hd ADHD s children (4, 5). Studies of referred nd nonreferred dults with ADHD hve lso documented high risk for psychoctive substnce use disorder (6, 7). Most recently, Kessler nd collegues (8) reported results from the Ntionl Comorbidity Survey indicting tht dults with ADHD were t significntly higher risk for ny substnce use disorder nd prticulrly drug dependence compred to respondents without ADHD. Excess rtes of ADHD hve lso been seen in dolescents nd dults with psychoctive substnce use disorder. DeMilio (9) reported tht 25% of inptient dolescents with psychoctive substnce use disorder hd ADHD. Results from the Methods for the Epidemiology of Child nd Adolescent Mentl Disorders (MECA) study (10) reveled tht incresed substnce use ws ssocited with disruptive behvior mong children nd dolescents. The vilble literture shows tht dolescent nd dult offspring of prents with psychoctive substnce use disorder re t incresed risk for the disorder s well s bnorml cognitive nd behviorl trits suggestive of ADHD s well s elevted rtes of ADHD compred with children of comprison prents (11 13). Wilens et l. (14) reported tht 23% of children of opioid-dependent prents hd scores on the ttention problems subscle of the Child Behvior Checklist tht were highly suggestive of ADHD. The link between ADHD nd psychoctive substnce use disorder hs lso been seen in fmily members of children with ADHD. Morrison nd Stewrt (15) nd Cntwell (16) reported elevted rtes of lcoholism in prents nd second-degree reltives of children with ADHD. Similr findings hve been seen in two lrge double-blind fmily genetic studies of ADHD tht showed higher rtes of psychoctive substnce use disorder in the reltives of boys (17) nd girls (18) with ADHD. This rticle is the subject of CME course (p. 159), is fetured in this month s AJP Audio, nd is discussed in n editoril by Dr. Adler on p. 11. Am J Psychitry 165:1, Jnury 2008 jp.psychitryonline.org 107

2 RISK ANALYSES OF ADHD AND SUBSTANCE USE Despite the contribution of this literture suggesting fmilil ssocition between ADHD nd psychoctive substnce use disorder, severl uncertinties remin. Mny studies did not specificlly exmine the dignosis of ADHD, did not use contemporneous dignostic criteri, did not dequtely ttend to the heterogeneity of psychoctive substnce use disorder, nd did not ttempt to disentngle the type of fmilil ssocition tht my be opernt between psychoctive substnce use disorder nd its subtypes with ADHD. In one of the few studies of its kind, Milberger et l. (19) reported results from fmilil risk nlysis of longitudinl smple of boys with nd without ADHD followed into their dolescent yers. Although the results were suggestive of independent trnsmission of ADHD nd psychoctive substnce use disorder, vrible expressivity could not be ruled out. However, becuse the probnds in this nlysis were dolescents nd they were still trnsiting through the period of risk for psychoctive substnce use disorder, these findings require repliction in older smples. To this end, we reexmined ptterns of fmilil ssocition between ADHD nd psychoctive substnce use disorder in the sme group tht we previously studied in dolescence (19) t the 10-yer follow-up into young dult yers with dded ttention to subtypes of psychoctive substnce use disorder. We conducted fmilil risk nlyses bsed on models proposed by Puls et l. (20), testing hypotheses bout the fmilil reltionship between ADHD nd psychoctive substnce use disorder. Specificlly, we tested three competing hypotheses: 1) ADHD nd ddiction to drugs nd lcohol re etiologiclly independent, 2) ADHD nd ddiction to drugs nd lcohol represent distinct fmilil subtype, nd 3) ADHD nd ddiction to drugs nd lcohol shre common fmilil etiologic fctors (vrible expressivity hypothesis). Method Subjects Subjects were derived from longitudinl cse-control fmily study of ADHD (18, 21, 22). At bseline, we scertined Cucsin boys ges 6 17 yers with (N=140) nd without (N=120) DSM-III-R ADHD from peditric nd psychitric clinics. Previously, this group ws followed up t 1 yer nd 4 yers fter bseline. The present study reports on the 10-yer follow-up of this group, in which 112 ADHD nd 105 comprison probnds were successfully rescertined. First-degree reltives of these probnds included mothers (N=217), fthers (N=216), nd siblings (N=310). The prents were ssessed t bseline only (becuse they hd pssed the ge of risk for most psychopthology), wheres the siblings were ssessed t bseline (N=243), 1-yer follow-up (N= 251), 4-yer follow-up (N=272), nd 10-yer follow-up (N= 296). At bseline, the 1-yer follow-up, nd the 4-yer follow-up, dignostic ssessments of ADHD were bsed on the Schedule for Affective Disorders nd Schizophreni for School-Age Children: Epidemiologic Version (K-SADS-E) (23) for DSM-III-R. The sources providing index children nd the scertinment procedures re detiled in previous publictions (18, 21, 22). The prents nd dult offspring provided written informed consent to prticipte, nd the prents lso provided consent for offspring under the ge of 18. The children nd dolescents provided written ssent to prticipte. The humn reserch committee t Msschusetts Generl Hospitl pproved this study. Follow-Up Assessment Procedures Lifetime psychitric ssessments t the 10-yer follow-up relied on the K-SADS-E (Epidemiologic Version) (24) for subjects younger thn 18 yers of ge nd the Structured Clinicl Interview for DSM-IV (SCID) (25) (supplemented with modules from the K- SADS-E to ssess childhood dignoses) for subjects 18 yers of ge nd older. Ten percent of the probnds (21 of 217) nd 12% of the reltives (86 of 743) were younger thn 18 yers of ge t their lst ssessment. We conducted direct interviews with the subjects nd indirect interviews with their mothers (i.e., the mothers completed the interview bout their offspring). We combined dt from direct nd indirect interviews by considering dignostic criterion positive if it ws endorsed in either interview. The interviewers were blind to the subject s scertinment group, the scertinment site, nd ll prior ssessments. Detils of interviewer trining nd the relibility of dignoses re provided in previous publiction (22). We considered disorder positive if DSM-IV dignostic criteri were unequivoclly met. A committee of bord-certified child nd dult psychitrists who were blind to the subject s ADHD sttus, referrl source, nd ll other dt resolved dignostic uncertinties. Dignoses presented for review were considered positive only when the committee determined tht dignostic criteri were met to cliniclly meningful degree. Socioeconomic sttus ws mesured with the 5-point Hollingshed scle (26). Sttisticl Anlysis First, we compred chrcteristics (onset, durtion, severity, etc.) of psychoctive substnce use disorder (ny lcohol buse, drug buse, lcohol dependence, or drug dependence), lcohol dependence, nd drug dependence between the ADHD nd comprison probnds with logistic regression, liner regression, or negtive binomil regression depending on the distribution of the outcome. Second, we conducted three sets of fmilil risk nlyses. In the first set of nlyses, we compred four groups of reltives defined by the probnds ADHD nd psychoctive substnce use disorder sttus (i.e., neither, ADHD lone, psychoctive substnce use disorder lone, both ADHD nd psychoctive substnce use disorder). Using Cox proportionl hzrds models, we compred the reltives of the four probnd groups on estimted rtes of ADHD nd psychoctive substnce use disorder. Using Cox models, cosegregtion ws estblished if the presence of ADHD in the reltive significntly incresed the risk for psychoctive substnce use disorder in the sme reltive within the subset of fmilies hving probnd with both ADHD nd psychoctive substnce use disorder. We tested for nonrndom mting of ADHD nd substnce use disorders with Fisher s exct test. In the second set of nlyses, we repeted the nlyticl pproch described bove except tht we used lcohol dependence to define the probnd groups nd s n outcome in the reltives. In the third set of nlyses, we used drug dependence to define the probnd groups nd s n outcome in the reltives. Finlly, we ssessed whether the risk for lcohol nd drug dependence in the reltives ws specific to lcohol or drug dependence in the probnd using Cox proportionl hzrds models. To ccount for the nonindependence of fmily members, we used the Huber (27) correction to produce robust vrinces for ll sttisticl tests using fmily members. All tests were two-tiled with lph set t jp.psychitryonline.org Am J Psychitry 165:1, Jnury 2008

3 BIEDERMAN, PETTY, WILENS, ET AL. TABLE 1. Demogrphic Chrcteristics of Attention Deficit Hyperctivity Disorder (ADHD) nd Comprison Probnds nd Their First-Degree Reltives ADHD Probnds Comprison Probnds Anlysis Age (yers) Age (yers) Vrible N Men SD N Men SD Test df p Age t lst ssessment (yers) Probnds t= Mothers t= Fthers t= Siblings t= Fmily socioeconomic sttus (26) χ 2 = TABLE 2. Substnce Use in Probnds With nd Without Attention Deficit Hyperctivity Disorder (ADHD) Vrible ADHD Probnds (N=112) Comprison Probnds (N=105) Anlysis N % N % z df p Psychoctive substnce use disorder Severe impirment Men SD Men SD Test df p Onset (yers) t= Durtion (yers) t= Number of ffected reltives in fmily z= Onset in ffected reltives (yers) t= N % N % z df p Alcohol dependence Men SD Men SD Test df p Onset (yers) t= Durtion (yers) t= Number of ffected reltives in fmily z= Onset in ffected reltives (yers) t= N % N % Test df p Severe impirment z= Drug dependence z= Mrijun z= Cocine/stimulnts z= Sedtives Fisher s exct test 1.00 Ketmine Fisher s exct test 0.32 Men SD Men SD Test df p Onset (yers) t= Durtion (yers) t= Number of ffected reltives in fmily z= Onset in ffected reltives (yers) t= N % N % Test df p Severe impirment z= Alcohol plus drug dependence b z= Fisher s exct test 0.06 Hospitlized for substnce use Denomintor is number of subjects with drug dependence. b Denomintor is number of subjects with lcohol nd/or drug dependence. Results Demogrphic Chrcteristics Becuse probnds with ADHD were significntly younger thn comprison probnds, probnd ge ws controlled for in ll nlyses (Tble 1). Detils on ttrition re provided in previous publiction (22). Chrcteristics of Substnce Use in ADHD nd Comprison Probnds Rtes of psychoctive substnce use disorder (lcohol buse, drug buse, lcohol dependence, or drug dependence) did not differ between ADHD nd comprison probnds, but ADHD probnds hd significntly erlier onset, longer durtion, higher rtes of severe impirment ssocited with psychoctive substnce use disorder, nd more ffected first-degree reltives in reltion to comprison probnds (Tble 2). Rtes of both lcohol nd drug dependence were significntly higher in the ADHD probnds thn in the comprison probnds, s well s the number of first-degree reltives ffected with the sme disorder. Fmilil Risk for ADHD nd Psychoctive Substnce Use Disorder Four groups were used for the fmilil risk nlysis of psychoctive substnce use disorder nd ADHD: the reltives of 46 comprison probnds without psychoctive substnce use disorder (comprison probnds, N=153), Am J Psychitry 165:1, Jnury 2008 jp.psychitryonline.org 109

4 RISK ANALYSES OF ADHD AND SUBSTANCE USE FIGURE 1. Risk for Attention Deficit Hyperctivity Disorder nd Substnce Use in Reltives by Probnd Dignosis Psychoctive Substnce Use Disorder Alcohol Dependence Drug Dependence Probnd s dignosis Probnd s dignosis Probnd s dignosis ADHD ADHD ADHD Comprison Comprison Comprison Comprison nd psychoctive substnce use disorder ADHD nd psychoctive substnce use disorder Comprison nd lcohol dependence ADHD nd lcohol dependence Comprison nd drug dependence ADHD nd drug dependence Risk for ADHD in reltives,b Risk for ADHD in reltives,b,b Risk for ADHD in reltives Age-Adjusted Rte Risk for psychoctive substnce use disorder in reltives Risk for lcohol dependence in reltives c Risk for drug dependence in reltives Age (yers) p<0.05 versus comprison subjects. b p<0.05 versus comprison subjects plus substnce use disorder subjects. c p<0.05 versus subjects with ADHD. the reltives of 59 comprison probnds with psychoctive substnce use disorder (comprison probnds plus psychoctive substnce use disorder, N=205), the reltives of 44 ADHD probnds without psychoctive substnce use disorder (ADHD, N=149), nd the reltives of 68 ADHD probnds with psychoctive substnce use disorder (ADHD plus psychoctive substnce use disorder, N=236). Risk for ADHD in Reltives Figure 1 (left) shows tht ge-djusted rtes of ADHD in the ADHD plus psychoctive substnce use disorder nd ADHD groups were significntly higher in reltion to comprison probnds (16% nd 23% versus 5%; hzrd rtio= 1.7, 95% confidence intervl [CI]= , p<0.001, nd hzrd rtio=1.8, CI= , p=0.002, respectively). The ADHD plus psychoctive substnce use disorder group lso hd significntly higher rtes of ADHD in reltion to the comprison probnds plus the psychoctive substnce use disorder group (23% versus 8%, hzrd rtio= 1.7, CI= , p=0.004). Risk for Psychoctive Substnce Use Disorder in Reltives The ADHD plus psychoctive substnce use disorder, ADHD, nd comprison probnds plus psychoctive substnce use disorder groups ll hd significntly higher ge-djusted rtes of psychoctive substnce use disorder in reltion to the comprison probnds (48%, 44%, nd 45% versus 30%; hzrd rtio=1.2, CI= , p=0.001; hzrd rtio=1.3, CI= , p=0.02; nd hzrd rtio=1.7, CI= , p=0.02, respectively; Figure 1, left). There ws no evidence for cosegregtion in the ADHD plus psychoctive substnce use disorder group (68% psychoctive substnce use disorder in subjects with ADHD versus 48% psychoctive substnce use disorder in subjects without ADHD, p=0.08). Fmilil Risk for ADHD nd Alcohol Dependence The fmilil risk nlysis of lcohol dependence nd ADHD used four groups: the reltives of 88 comprison 110 jp.psychitryonline.org Am J Psychitry 165:1, Jnury 2008

5 BIEDERMAN, PETTY, WILENS, ET AL. probnds without lcohol dependence (comprison probnds, N=294), the reltives of 17 comprison probnds with lcohol dependence (comprison probnds plus lcohol dependence, N=64), the reltives of 83 ADHD probnds without lcohol dependence (ADHD, N=283), nd the reltives of 29 ADHD probnds with lcohol dependence (ADHD plus lcohol dependence, N=102). Risk for ADHD in Reltives Figure 1, middle, shows tht the rtes of ADHD in the ADHD plus lcohol dependence nd ADHD groups were significntly higher in reltion to comprison probnds (18% nd 26% versus 8%; hzrd rtio=1.6, CI= , p<0.001, nd hzrd rtio=1.6, CI= , p=0.001, respectively) nd comprison probnds plus lcohol dependence (18% nd 26% versus 4%; hzrd rtio=3.1, CI= , p=0.002, nd hzrd rtio=6.6, CI= , p=0.006, respectively). Risk for Alcohol Dependence in Reltives The ADHD plus lcohol dependence group hd significntly higher ge-djusted rte of lcohol dependence in reltives in reltion to comprison probnds (42% versus 18%; hzrd rtio=1.4, CI= , p<0.001), comprison probnds plus lcohol dependence (42% versus 21%; hzrd rtio=1.5, CI= , p=0.05), nd ADHD groups (42% versus 23%; hzrd rtio=2.4, CI= , p=0.002; Figure 1, middle). There ws no evidence for cosegregtion in the ADHD plus lcohol dependence group (46% lcohol dependence in probnds with ADHD versus 40% lcohol dependence in probnds without ADHD, p=0.08). Fmilil Risk for ADHD nd Drug Dependence The fmilil risk nlysis of drug dependence nd ADHD used four groups: the reltives of 94 comprison probnds without drug dependence (comprison probnds, N=321), the reltives of 11 comprison probnds with drug dependence (comprison probnds plus drug dependence, N= 37), the reltives of 89 ADHD probnds without drug dependence (ADHD probnds, N=309), nd the reltives of 23 ADHD probnds with drug dependence (ADHD probnds plus drug dependence, N=76). Risk for ADHD in Reltives Figure 1 (right) shows tht the rtes of ADHD in the ADHD plus drug dependence, ADHD, nd comprison probnds plus drug dependence groups were significntly higher in reltion to the comprison probnds (21%, 20%, nd 22% versus 5%; hzrd rtio=1.7, CI= , p<0.001; hzrd rtio=2.1, CI= , p<0.001; nd hzrd rtio= 8.0, CI= , p<0.001, respectively). Risk for Drug Dependence in Reltives Likewise, Figure 1 (right) shows tht the rtes of drug dependence were significntly higher in the ADHD plus drug dependence, ADHD, nd comprison probnds plus drug dependence groups in reltion to comprison probnds (14%, 12%, nd 17% versus 5%; hzrd rtio=1.4, CI= , p=0.02; hzrd rtio=1.5, CI= , p=0.04; nd hzrd rtio=5.0, CI= , p=0.03, respectively). There ws no evidence for cosegregtion in the ADHD plus drug dependence group (21% drug dependence in subjects with ADHD versus 12% drug dependence in subjects without ADHD, p=0.34). Nonrndom Rting Among Prents There ws no evidence for nonrndom mting of prentl ADHD nd prentl psychoctive substnce use disorder, lcohol dependence, or drug dependence (ll p>0.15). Specific Versus Common Risk for Dependence The following four groups were used: the reltives of 156 probnds without lcohol dependence nd without drug dependence (no dependence, N=528), the reltives of 27 probnds with lcohol dependence but without drug dependence (lcohol dependence, N=102), the reltives of 15 probnds with drug dependence but without lcohol dependence (drug dependence, N=49), nd the reltives of 19 probnds with lcohol nd drug dependence (lcohol plus drug dependence, N=64). Risk for Alcohol Dependence in Reltives Figure 2 (top) shows tht the lcohol dependence nd lcohol plus drug dependence groups hd significntly higher rtes of lcohol dependence compred to the no dependence group (34% nd 32% versus 21%; hzrd rtio=2.1, CI= , p=0.009, nd hzrd rtio=1.2, CI= , p=0.02, respectively). Risk for Drug Dependence in Reltives Figure 2 (top) shows tht the drug dependence group hd significntly higher rte of drug dependence compred to the no dependence (26% versus 9%; hzrd rtio= 1.9, CI= , p<0.001) nd lcohol dependence (26% versus 10%; hzrd rtio=3.0, CI= , p=0.01) groups. These ssocitions did not vry significntly by the ADHD sttus of the probnd (both interction effects, p>0.05). Effect of Mood Disorders on Risk for Substnce Use A secondry nlysis ws conducted to determine if the risk for lcohol nd drug dependence ws medited by mood disorders. Independent of probnd ADHD nd lcohol dependence sttus, neither probnd mjor depression with severe impirment (p=0.25) nor probnd bipolr disorder (p=0.09) significntly dded to the risk for lcohol dependence in reltives. Independent of probnd ADHD nd drug dependence sttus, probnd mjor depression with severe impirment did not significntly predict drug dependence in the reltives (p=0.26), but probnd bipolr disorder significntly dded to the risk for drug dependence in the reltives (hzrd rtio=3.4, CI= , p=0.001). Am J Psychitry 165:1, Jnury 2008 jp.psychitryonline.org 111

6 RISK ANALYSES OF ADHD AND SUBSTANCE USE FIGURE 2. Risk for Addictions in Reltives by Probnd Dignosis Age-Adjusted Rte p<0.05 versus no dependence. b p<0.05 versus lcohol dependence. Discussion Probnd s dignosis No dependence Drug dependence Alcohol dependence Alcohol nd drug dependence Risk for lcohol dependence in reltives Risk for drug dependence in reltives Age (yers) In systemtic evlution of the fmilil reltionship between ADHD nd psychoctive substnce use disorder with well-chrcterized longitudinl group of ADHD boys s dults nd their first-degree reltives, we found the following: 1. ADHD in the probnd ws consistently ssocited with significntly incresed risk for ADHD in reltives irrespective of comorbidity with psychoctive substnce use disorder 2. ADHD in the probnd lso predicted psychoctive substnce use disorder nd drug dependence in the reltives 3. Drug dependence in comprison probnds incresed the risk for ADHD in reltives 4. Alcohol dependence in reltives ws predicted only by ADHD probnds with comorbid lcohol dependence,b 5. Both lcohol dependence nd drug dependence bred true in fmilies without evidence of common risk between these disorders. Although probnds with nd without ADHD did not differ on the bsolute rtes of the combined ctegory of ny psychoctive substnce use disorder, probnds with ADHD hd n erlier onset, longer durtion, nd higher rtes of severely impiring psychoctive substnce use disorder s well s higher rtes of lcohol nd drug dependence. Moreover, probnds with ADHD hd more first-degree reltives with psychoctive substnce use disorder, lcohol, nd drug dependence in reltion to comprison probnds. Tken together, these findings indicte tht the type of psychoctive substnce use disorder tht develops in the context of ADHD is very morbid form of the disorder nd support the hypothesis tht ADHD is fmilil risk fctor for psychoctive substnce use disorder. The rtes of substnce use in the reltives of comprison probnds were consistent with the Ntionl Comorbidity Survey (28) for psychoctive substnce use disorder (32.1% versus 26.6%, respectively) nd lcohol dependence (13.7% versus 14.1%, respectively). The reltives of comprison probnds hd 5.6% prevlence of drug dependence, in between the 7.5% prevlence reported by the Ntionl Comorbidity Survey (28) nd the 2.6% prevlence recently reported by Compton nd collegues (29). For comprison probnds, the rtes of lcohol nd drug dependence were consistent with the Ntionl Comorbidity Survey (28), but the rte of the combined ctegory of psychoctive substnce use disorder ws twice s high. Although the resons for this high rte of psychoctive substnce use disorder in comprison probnds re not entirely cler, it ws driven minly by elevted rtes of lcohol buse tht my reflect the high risk for binge drinking in young dults in this ge rnge. For exmple, the Hrvrd School of Public Helth 1999 College Alcohol Study (30) found tht 44% of college students were binge drinkers, which ws the sme percentge of our comprison probnds with lcohol buse (44%, 46 of 105). ADHD in the probnd consistently incresed the risk for ADHD in reltives irrespective of psychoctive substnce use disorder sttus. The finding tht the risk for psychoctive substnce use disorder in reltives ws incresed in ADHD probnds with nd without psychoctive substnce use disorder is consistent with the vrible expressivity hypothesis tht ADHD nd psychoctive substnce use disorder shre common risk fctors. Evlution of the subtypes of psychoctive substnce use disorder reveled divergent ptterns of fmilil trnsmission for lcohol nd drug dependence. Findings reveled tht the risk for lcohol dependence ws only elevted in the reltives of probnds with comorbid ADHD plus lcohol dependence. These results, together with the bsence of cosegregtion nd nonrndom mting between ADHD nd lcohol dependence, fit best with the 112 jp.psychitryonline.org Am J Psychitry 165:1, Jnury 2008

7 BIEDERMAN, PETTY, WILENS, ET AL. hypothesis of independent trnsmission between these disorders, with the cvet tht the risk for lcohol dependence exists only in the context of fmilies with lcohol dependence nd ADHD. In the event tht there hd been cosegregtion of ADHD nd lcohol dependence, the findings would hve better fit with the hypothesis of fmily subtype. On the other hnd, the risk for drug dependence ws consistent with the vrible expressivity hypothesis tht the two disorders shre common fmilil determinnts. Specificlly, the rtes of ADHD were eqully elevted in the reltives of probnds with ADHD, drug dependence, or both nd significntly higher thn the rte of ADHD in comprison reltives. Likewise, the reltives of probnds with ADHD, drug dependence, or both hd significntly higher rtes of drug dependence compred to the reltives of comprison probnds but similr rtes of drug dependence compred to ech other. Common risks my involve dopmine genes (31) tht ffect ttention nd rousl s well s the rewrd pthwys ssocited with drug dependence. Due to our differentil findings for lcohol nd drug dependence, genetic studies of ADHD my benefit from understnding the biologicl nd genetic differences between lcohol nd drug dependence. Alterntively, ADHD nd drug dependence my shre common environmentl fctor nd hve distinct genetic cuses. These results re lso consistent with findings by our group (32) showing tht in reltion to comprison probnds, dult subjects with ADHD exhibited greter risk for drug buse or dependence (8% versus 27%) thn for lcohol buse or dependence (16% versus 31%). Mnnuzz et l. (5) lso showed tht children with ADHD s dults hve high risk for drug use disorders nd not lcohol use disorders. The rtes of lcohol dependence nd drug dependence were selectively higher in the reltives of probnds with the sme dignosis. This finding suggests tht the risk for lcohol nd drug dependence in reltives is specific to the type of ddiction fflicting the probnds nd is consistent with findings from Merikngs et l. (33), Bierut et l. (34), nd Milberger et l. (35), which rgue for specific nd independent risks for lcohol nd drug dependence. However, Nurnberger nd collegues (36) suggested tht lcohol nd drug dependence shre common mechnisms within some fmilies. Additionl work using community smples my resolve these differences becuse discrepnt findings could be due to unique spects of cliniclly scertined smples. Our findings should be interpreted in the context of severl limittions. Despite significnt differences between ADHD nd comprison fmilies in socioeconomic sttus, our nlyses did not control for socioeconomic sttus. Although future studies should help elucidte the reltionship between socioeconomic sttus, ADHD, nd psychoctive substnce use disorder, socioeconomic sttus my not be true covrite becuse the outcome (substnce use disorders) could ffect the covrite (fmily socioeconomic sttus) on mjority of the units of nlysis (prents). Our secondry nlysis further confirmed tht lcohol dependence is independently trnsmitted becuse probnd mood disorders did not ffect the risk for lcohol dependence in the reltives. However, the sme nlysis suggested tht the risk for drug dependence in the reltives could be ccounted for by comorbid bipolr disorder in the probnds. Future studies should ssist in determining the precise nture of the vribly expressed risk for drug dependence. In ddition, becuse mrijun ws the prepondernt drug of dependence in the probnds, our findings of vrible expressivity my not generlize to other drugs. Another potentil source of bis stems from the indirect psychitric ssessments with the mothers bout the probnds nd their siblings. This method my hve led to n underrepresenttion of psychopthology in the children. In ddition, lthough the probnds nd their siblings were ssessed t bseline nd follow-up ssessments, the prents were ssessed only t bseline. Thus, it is possible tht dditionl cses of substnce use disorders emerged in the prents during the 10-yer follow-up period, lthough the use of Cox models to clculte ge-djusted rtes somewht mitigtes this concern. Our group ws scertined with DSM-III-R criteri, so the findings my hve differed hd DSM-IV been used. However, Biedermn nd collegues (37) showed tht 93% of children with DSM-III-R dignosis lso received DSM-IV dignosis. Finlly, community-bsed studies should determine if these findings extend to the generl popultion. Studies should lso determine if smples of femles with ADHD would yield consistent results. In summry, in group of peditriclly nd psychitriclly referred children nd dolescents with ADHD, fmilil risk nlyses suggest tht the ssocition between ADHD nd drug nd lcohol dependence re substnce specific, nd they re most consistent with the hypothesis of vrible expressivity for drug dependence nd independent trnsmission for lcohol dependence. Received Mrch 7, 2007; revision received June 14, 2007; ccepted June 29, 2007 (doi: /ppi.jp ). From the Clinicl nd Reserch Progrm in Peditric Psychophrmcology, Psychitry Deprtment, Msschusetts Generl Hospitl. Address correspondence nd reprint requests to Dr. Biedermn, Clinicl nd Reserch Progrm in Peditric Psychophrmcology, Msschusetts Generl Hospitl, 55 Fruit St., Wrren 705, Boston, MA 02114; jbiedermn@prtners.org (e-mil). Dr. Biedermn hs received reserch support from, hs been speker for, or hs been on the dvisory bords for Shire, Eli Lilly, Pfizer, McNeil, Abbott, Neuroserch, Bristol-Myers Squibb, New River, Cephlon, Jnssen, Novrtis, UCB Phrm, Astr-Zenec, Forest, Glxo-Smith Kline, Neuroserch, the Stnley Medicl Institute, the Lilly Foundtion, the Prechter Foundtion, NIMH, the Ntionl Institute of Child Helth nd Humn Development, Cephlon, Novrtis, nd the Ntionl Institute on Drug Abuse. Dr. Wilens hs received reserch support from, hs been speker for, or hs been on the dvisory bords for Abbott, Ortho-McNeil, Eli Am J Psychitry 165:1, Jnury 2008 jp.psychitryonline.org 113

8 RISK ANALYSES OF ADHD AND SUBSTANCE USE Lilly, the Ntionl Institute on Drug Abuse, Neuroserch, Novrtis, Shire, Glxo-Smith Kline, nd Pfizer. Dr. Mick hs received grnt support from McNeil Peditrics nd NIMH nd is consultnt for Jnssen nd Pfizer. Dr. Frone hs received reserch support from, hs been speker for, or hs been on the dvisory bords for Eli Lilly, McNeil, Shire US, Novrtis, Noven, Cephlon, NIMH, the Ntionl Institute of Child Helth nd Humn Development, nd the Ntionl Institute of Neurologicl Disorders nd Stroke. The remining uthors report no competing interests. Supported by the following grnts from the United Sttes Public Helth Service (Ntionl Institute of Child Helth nd Humn Development): 5R01 HD (to Dr. Biedermn), 5RK24 DA (to Dr. Wilens), nd R01 DA14419 (to Dr. Wilens). References 1. Crroll K, Rounsville B: History nd significnce of childhood ttention deficit disorder in tretment-seeking cocine busers. Compr Psychitry 1993; 34: Kminer Y: Clinicl implictions of the reltionship between ttention-deficit hyperctivity disorder nd psychoctive substnce use disorders. Am J Addict 1992; 1: Wilens T, Biedermn J, Spencer T, Frnces R: Comorbidity of ttention deficit hyperctivity nd psychoctive substnce use disorders. Hosp Community Psychitry 1994; 45: Hechtmn L, Weiss G: Controlled prospective fifteen yer follow-up of hyperctives s dults: non-medicl drug nd lcohol use nd nti-socil behviour. Cn J Psychitry 1986; 31: Mnnuzz S, Gittelmn R, Klein R, Bongur N, Mlloy P, Gimpino TL, Addlli KA: Hyperctive boys lmost grown up, V: repliction of psychitric sttus. Arch Gen Psychitry 1991; 48: Shekim WO, Asrnow RF, Hess E, Zuch K, Wheeler N: A clinicl nd demogrphic profile of smple of dults with ttention deficit hyperctivity disorder, residul stte. Compr Psychitry 1990; 31: Biedermn J, Frone SV, Spencer T, Wilens T, Normn D, Lpey KA, Mick E, Lehmn BK, Doyle A: Ptterns of psychitric comorbidity, cognition, nd psychosocil functioning in dults with ttention deficit hyperctivity disorder. Am J Psychitry 1993; 150: Kessler RC, Adler L, Brkley R, Biedermn J, Conners CK, Demler O, Frone SV, Greenhill LL, Howes MJ, Secnik K, Spencer T, Ustun TB, Wlters EE, Zslvsky AM: The prevlence nd correltes of dult ADHD in the United Sttes: results from the Ntionl Comorbidity Survey Repliction. Am J Psychitry 2006; 163: DeMilio L: Psychitric syndromes in dolescent substnce busers. Am J Psychitry 1989; 146: Kndel D, Johnson J, Bird H, Cnino G, Goodmn S, Lhey B, Reiger D, Schwb-Stone M: Psychitric disorders ssocited with substnce use mong children nd dolescents: findings from the Methods for the Epidemiology of Child nd Adolescent Mentl Disorders (MECA) study. J Abnorm Child Psychol 1997; 25: Erls F, Reich W, Jung KG, Cloninger R: Psychopthology in children of lcoholic nd ntisocil prents. Alcohol Clin Exp Res 1988; 12: Json Aronson H, Gilbert A: Predolescent sons of mle lcoholics. Arch Gen Psychitry 1963; 8: Steinhusen H, Gobel D, Nestler V: Psychopthology in the offspring of lcoholic prents. J Am Acd Child Adolesc Psychitry 1984; 23: Wilens T, Biedermn J, Kiely K, Bredin E, Spencer T: Pilot study of behviorl nd emotionl disturbnces in the high-risk children of prents with opioid dependence. J Am Acd Child Adolesc Psychitry 1995; 34: Morrison JR, Stewrt MA: A fmily study of the hyperctive child syndrome. Biol Psychitry 1971; 3: Cntwell DP: Psychitric illness in the fmilies of hyperctive children. Arch Gen Psychitry 1972; 27: Biedermn J, Frone SV, Keenn K, Knee D, Tsung MT: Fmily-genetic nd psychosocil risk fctors in DSM-III ttention deficit disorder. J Am Acd Child Adolesc Psychitry 1990; 29: Biedermn J, Frone SV, Keenn K, Benjmin J, Krifcher B, Moore C, Sprich-Buckminster S, Uggli K, Jellinek MS, Steingrd R, Spencer T, Normn D, Kolodny R, Krus I, Perrin J, Keller MB, Tsung MT: Further evidence for fmily-genetic risk fctors in ttention deficit hyperctivity disorder: ptterns of comorbidity in probnds nd reltives in psychitriclly nd peditriclly referred smples. Arch Gen Psychitry 1992; 49: Milberger S, Frone SV, Biedermn J, Chu MP, Wilens T: Fmilil risk nlysis of the ssocition between ttention-deficit/hyperctivity disorder nd psychoctive substnce use disorders. Arch Peditr Adolesc Med 1998; 152: Puls DL, Towbin KE, Leckmn JF, Zhner GE, Cohen DJ: Gilles de l Tourette s syndrome nd obsessive-compulsive disorder: evidence supporting genetic reltionship. Arch Gen Psychitry 1986; 43: Biedermn J, Frone S, Milberger S, Guite J, Mick E, Chen L, Mennin D, Mrrs A, Ouellette C, Moore P, Spencer T, Normn D, Wilens T, Krus I, Perrin J: A prospective 4-yer follow-up study of ttention-deficit hyperctivity nd relted disorders. Arch Gen Psychitry 1996; 53: Biedermn J, Monuteux M, Mick E, Spencer T, Wilens T, Silv J, Snyder L, Frone SV: Young dult outcome of ttention deficit hyperctivity disorder: controlled 10 yer prospective followup study. Psychol Med 2006; 36: Orvschel H, Puig-Antich J: Schedule for Affective Disorders nd Schizophreni for School-Age Children Epidemiologic Version (K-SAD-E), 4th revision. Ft Luderdle, Fl, Nov University, Orvschel H: Schedule for Affective Disorder nd Schizophreni for School-Age Children Epidemiologic Version (K-SAD-E), 5th ed. Ft Luderdle, Fl, Nov Southestern University, Center for Psychologicl Studies, First M, Spitzer R, Gibbon M, Willims J: Structured Clinicl Interview for DSM-IV Axis I Disorders. Wshington, DC, Americn Psychitric Press, Hollingshed AB: Four Fctor Index of Socil Sttus. New Hven, Conn, Yle Press, Huber PJ: The behvior of mximum likelihood estimtes under non-stndrd conditions. Proceedings of the Fifth Berkeley Symposium on Mthemticl Sttistics nd Probbility 1967; 1: Kessler R, McGongle K, Zho S, Nelson C, Hughes M, Eshlemn S, Wittchen H, Kendler K: Lifetime nd 12 month prevlence of DSM-III-R psychitric disorders in the United Sttes: results from the Ntionl Comorbidity Survey. Arch Gen Psychitry 1994; 51: Compton WM, Thoms YF, Stinson FS, Grnt BF: Prevlence, correltes, disbility, nd comorbidity of DSM-IV drug buse nd dependence in the United Sttes: results from the Ntionl Epidemiologic Survey on Alcohol nd Relted Conditions. Arch Gen Psychitry 2007; 64: Wechsler H, Lee JE, Kuo M, Lee H: College binge drinking in the 1990s: continuing problem: results of the Hrvrd School of Public Helth 1999 College Alcohol Study. J Am Coll Helth 2000; 48: jp.psychitryonline.org Am J Psychitry 165:1, Jnury 2008

9 BIEDERMAN, PETTY, WILENS, ET AL. 31. Frone SV, Perlis RH, Doyle AE, Smoller JW, Gorlnick J, Holmgren MA, Sklr P: Moleculr genetics of ttention deficit hyperctivity disorder. Biol Psychitry 2005; 57: Biedermn J, Wilens T, Mick E, Milberger S, Spencer TJ, Frone SV: Psychoctive substnce use disorder in dults with ttention deficit hyperctivity disorder (ADHD): effects of ADHD nd psychitric comorbidity. Am J Psychitry 1995; 152: Merikngs K, Stolr M, Stevens D, Goulet J, Preisig M, Fenton B, Zhng H, O Mlley S, Rounsville B: Fmilil trnsmission of substnce use disorders. Arch Gen Psychitry 1998; 55: Bierut L, Dinwiddie S, Begleiter H, Crowe R, Hesselbrock V, Nurnberger J, Porjesz B, Schuckit M, Reich T: Fmilil trnsmission of substnce dependence: lcohol, mrijun, cocine, nd hbitul smoking. Arch Gen Psychitry 1998; 55: Milberger S, Frone SV, Biedermn J, Chu MP, Feighner JA: Substnce use disorders in high-risk dolescent offspring. Am J Addict 1999; 8: Nurnberger JI Jr, Wiegnd R, Bucholz K, O Connor S, Meyer ET, Reich T, Rice J, Schuckit M, King L, Petti T, Bierut L, Hinrichs AL, Kupermn S, Hesselbrock V, Porjesz B: A fmily study of lcohol dependence: coggregtion of multiple disorders in reltives of lcohol-dependent probnds. Arch Gen Psychitry 2004; 61: Biedermn J, Frone SV, Weber W, Russell RL, Rter M, Prk K: Correspondence between DSM-III-R nd DSM-IV ttention deficit hyperctivity disorder (ADHD). J Am Acd Child Adolesc Psychitry 1997; 36: Am J Psychitry 165:1, Jnury 2008 jp.psychitryonline.org 115