Attention-Deficit Hyperactivity Disorder and Juvenile Mania: An Overlooked Comorbidity? JOSEPH BIEDERMAN, M.D., STEPHEN FARAONE, Pa.D., ERIC MICK, B.A, JANET WOZNIAK, M.D., LISA CHEN, B.A, CHERYL OUELLETTE, B.A., ABBE MARRS, B.A., PHOEBE MOORE, B.A., JENNIFER GARCIA, B.A., DOUGLAS MENNIN, B.A., aNb ELISE LELON, M.Eo. ABSTRACT Objective: To evaluate the psychiatie, cognitive, and functional comelates of atention-defct hyperactivity disorder (ADHD) children with and witiout comorbid bipolar dsordor (BPO). Method: DSWII-A structured dlagnostic Interviews, ‘and bind raters were used fo examine psychiatic diagnoses at baseline and 4-year follow-up in ADHD and contro! children. In addon, subjects were evaluated for cognitive, academic, social, school, and family functoning. Results: [BPD was diagnosed in 11% of ADHD chitéren at baseline and in an addtional 12% at 4year folow-up, These rates ‘wore significantly higher than those of controls at each assessment. ADHD children with comorbid BPD at ether baseline oF foiow-up assessment had significantly higher rates of adaltonal psychopathology, psychate hospitalization, and severely impaired psychosocial funconing than other ADHD children. Tho clinical picture of bipolarty was mostly Intable and mixed. ADHD children with comorbid BPO also had a very severe symptomatic pictur of ADHD as well 8 prototypical corelates ofthe disorder. Comorbidty between ADHD and BPD was not due to symptom overag. [ADHD children who developed BPD at the 4-year folow-up had higher inal rates of comorbidity, mare symptoms of |ADHD, worse scores on the CBCL, and a greater family history of mood disorder compared with nomBPD, ADHD cfldren. Conclusions: The results extend previous resuits documenting that children with ADHD are at increased risk of developing BPO with its associated severe morbidly, dysfunction, and incapactation. J Am. Acad. Child Adolesc. Peychiatry, 1996, 95(8)'997~1008. Key Words: bipolar disorder, atlertion-defct hyperactivity dsorder, comorbiy Reports in pediatric and adult samples document the co-occurrence of attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD), yet litte is known about the comorbid condition (Butler et al, 1995; Carlson, 1984; Potter, 1983; Poznanski et al., 1984), Butler et al. (1995) found high rates of BPD Aecpted Jaary 17, 1396. From te Pea Pochopharacelogy Unis, Pycitry Servic, Menace sexs Generel Hopi, Baton. Dru Biederman, Faraone, and Ween are the with the Diperoentof Phi, Harvand Metical Scot, Baran, Dr Parco is abo with the Harvard Inte of Phi, Epidemiol, and Genesio, Deparment of Prin, Harard Medi Schoo at Braco Wat Rexbury Vora: Afr Mac Cover and Masacbnets Heb Conte Boson. Mr. Mick i sho with te Deparonent of Epidemiology, Harsard ‘Seholof Pubs Heat, Bavon This work so pared in pert by NIMH grant ROL MEGI314-07 (Biederman). Reprint reacts 10 Dr. Bierman, Peiaric Pychepharcsligy Unit (ACC 725), Masacbases General Hap, Frit Soe, Boson, MA 02114: selephone (617) 7261737. '890-8567/96)3508-0997803.00/001996 by she American Academy ‘oF Child and Adolexcene Pech. J. AM, ACAD. CHILD ADOLESC. PSYCHIATRY. 35:8, AUGUST 1996 (22%) in a hospitalized sample of ADHD patients. ‘West et al. (1995) reported that 57% of adolescents with BPD also had ADHD. In an adule sample, ‘Winokur et al. (1993) showed that traits of childhood hyperactivity were more common among BPD patients and their BPD relatives compared with depressed pa- tients. These findings were consistent with the many case reports of bipolar children that noted a frequent co-occurrence between manic and ADHD symptom- atology (Potter, 1983; Poznanski et al., 1984). Consid- cring the severity of BPD, its comorbidity with ADHD can lead to a most severe clinical picture that can greatly influence diagnosis, prognosis, and treatment of ADHD children (Angold and Costello, 1993; Maser and Cloninger, 1990), making it of high clinical and scientific relevance. We do not know why there have been so few systematic studies of the overlap between ADHD and mania, but likely reasons are the prevailing skepticism about the very existence of childhood BPD (Goodwin 997BIEDERMAN ET AL. and Jamison, 1990) and the clinical difficulties in distinguishing ADHD from mania in children due to symptomatic overlap (Carlson, 1984). An additional source of diagnostic uncertainty is that childhood mania may present differently from its adule counterpart (Biederman et al, 1995; Cancwell and Carlson, 1983; Carlson, 1983; Davis, 1979; Feinstein and Wolpert, 1973; McGlashan, 1988). Notably, unlike adult BPD patients, manic children are seldom characterized by euphoric mood (Carlson, 1983, 1984). Rather, the most common mood disturbance in manic children has been characterized as irtitable, with “affective storms” or prolonged and aggressive temper outbursts (Davis, 1979). In addition, ic has been suggested that the course of childhood-onset BPD tends to be chronic and continuous rather than episodic and acute, as is characteristic of the adult disorder (Carlson, 1983, 1984; Feinstein and Wolpert, 1973; McGlashan, 1988). ‘Worniak et al. (1995a) examined 262 clinically referred preadolescent children and showed that (1) 16% met diagnostic criteria for mania; (2) the clinical picture in these children was predominantly irritable and mixed; (3) 98% of children meeting criteria for ‘mania met criteria for ADHD; and (4) children with ‘mania-like symptoms were at risk for major depression, psychosis, psychiatric hospitalization, and severely im- paired psychosocial functioning. These BPD children ‘were also found to have significant elevations in all of the clinical scales of the Child Behavior Checklist (CBCL) compared with other ADHD children, partic- ularly in Delinquent Behavior, Aggressive Behavior, Anxious/Depressed, and Thought Problems scales (Biederman et al., 1995). Taken together, these studies provided converging evidence that children who meet criteria for BPD had a severe psychiatric condition that manifested a wide range of psychopathology and dysfunction. ‘The significance of distinguishing mania in children and adolescents with ADHD goes beyond resolving a vexing nosological question. Although limited, the available data suggest thar children with ADHD plus BPD may account for a substantial number of child psychiatric hospitalizations and that they are plagued. with chronic psychiatric and psychosocial disability (Worniak et al, 1995a). ‘Thus, the identification of a subtype of comorbid ADHD plus mania would provide improved guidelines for diagnosis and, eventually, for 998 treatment. Since prophylactic pharmacotherapy can reduce the psychiatric and psychosocial morbidity asso- ciated with BPD, clarification of these issues could benefit the youngsters who suffer from this severe disorder. In this study we evaluate the psychiatric, cognitive, and functional correlates of ADHD children with and without comorbid BPD, using data from a 4-year family and follow-up study of ADHD (Biederman et al, 1996, in press). Our goal was to use the follow- up data to determine whether ADHD with comorbid BPD could be differentiated from other cases of ADHD based on course and outcome, We also sought to determine whether bipolar onsets during the follow- up period could be predicted by the baseline condition of the child (e., we would expect baseline major depression to predict subsequent BPD). We also hy- pothesized that children with both mania and ADHD would have the clinical features of both disorders and that the clinical picture of childhood mania would be irritable and mixed. METHOD Subjects ‘The otiginal sample included 2 tor of 260 children (140 ADHD and 120 normal controls) chosen from paychistrc and ‘onpsychiatic, pediatric stings (Biederman et al, 1992). Within tach setting, ADHD children and normal controls were included ‘We screened conteols only for the presence of ADHD. The psychiatric sample conscted of consecutively ascertained ourptients from the pool of existing and new referrals 0 a specialized child psychiatric service and medical pediatric clnie st the same instita- Yion. Eligible ADHD subjects met clinical criteria for the DSM TIER diagnosis of ADHD based on a standaed child prychiatrc ‘evaluation conducted by a child paychiacise ‘As previously reported (Biederman et al, 1992), eligible subjects ‘were Caucasian, non-Hispanic, male children and adolescents, 6 to 17 years of age, with an IQ grescer than 80. We exclded adopred and. sepchildren, children with major sensorimotor handicaps (paralysis, deafness, blindness), and children or parents with mental reeardation or very severe and unstable psychopathology (psychosis, tut, suiidality) that was active at the time of aivessment Subjects with a history of euch prychopathology were nor excluded, Alto, subjects from the lowest socioeconomic dass were excluded to avoid the confounds of extreme social adversity Measures Probande and thie relatives were assessed at baseline and then again | and 4 years later. We examined their parents at baseline ‘only. A proband was deined as having a family history ofa disorder ifa parent or sibling had the disorder ac the bacine aesesment. ll diagnostic assessments used DSIM-I-R-based structured interviews. J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 35:8, AUGUST 1996ADHD AND COMORBID MANIA IN A LONGITUDINAL STUDY Paychiauic asesiments of children seed on the Schedule for ‘Aletive Disorders and Schizophrenia for School Age Children Epidemiologic Version (K-SADS-E) (Orvaschel and Puig Andch 1987). We assed both life and cient diagnos, but only lime diagnose are wed in dis repore We chow this inezvien tecause i widely used exablshes DSM-II-R diagnoses, can be effecvly administered by clnkans or tsned interviewers, and fas esablted pschometic propeics. Diagnoses wore based on independent cteviews wh the mother ad rec erie of pobnds and siblings cucept for children younger than 12 Yeas Of age, who were not diel interviewed. Diagnose aesment of parca were ated on direc incrvews with each parent, the Stucrured Cina Inrevew for DSMC-II-R (SCID) (Spite, tt a, 1990, To ates childhood diagnoses in the pare, we “ministered untmodiied modules rom the K'SADS-E-At bac ind year 1 the sractaed iverviows essed Kft hetory of Pcp aye hes sen eel ie re Se de pe asanent "The incviewers had undergraduare dessin pryhology and were tained to high lve of tren eabliy. We compared ‘ cociclents of agreement by having tree expeenced, board eve child and edule psychiaritsdlgnose bjs om audio tepad interviews made by the avessment safe, Based’ on. 173 Ineervews the median K was 86 and forthe disorders of most, ‘eleranc othe atl, he values wete99 for ADHD, 93 for Conde dhorder, 83 for mijor depron, and 94 for BPD. Diagnoses having X values below the median were aleoel abuse (GD, ansoctl penonaiy (66), dyshymia (79), and obvesive compulve diotder (51). Ae Fuaone eta. (1995) reported in dla che 1-year teseretee values were 95 for ADHD, 6 for tear depeecion, and 7 for BPD, These imeraer and etectest ‘Evalce were all within the range dsrbed 2 substantial vo alert perfect by Landis and Koch (1977) "The imervcwerspurtipated fn Gillie, igotous training program lating 3 to 4 months Tsning included mastery of the TEerumens,leiming abour DSMCHER cera watching taining taper obectingincvicws peformed by expedenced rater and ‘ating several sbjecs under the supervision ofthe project coordina tor Throughout the study, the Interviewers were supervied by beard cried child and adolescent poyhiaice, Ths supevion included weely mectings and additonal consultations at needed Before doing sudy imendews, interviewers must have achiced igh level of imerratreliblcy with thes pychintie, During the wendy, all inmrviews were audioaped for random, quai concl atsesiments bythe supervising pychiatns Tneddton te pebnne des ye seed dein meus of pychopathology wih the CBCL, Fall Sede 1. based. on the’ Vocabulary and Block Design sues from the Wechder ineligence ess (Suter, 1988), social functioning withthe Glob ‘Asesment of Functoning Scale ofthe DSMCHIER socioeconomic ttaus (Hollngshead, 1975), divorce or separation of parents in ftmily of origin special las placement a eported bythe pure, and peychiaic hepialcaion as reported by the parent All folow up avesments were bind t bueline dat colletied on the ‘ane abject Diagnostic Procedures ‘The interviewers were instructed to take extensive notes about the symptoms for each disorder. For evry diagnosis, information vas gathered reading she ages at onset and oft of mpm number of episodes, and treatment history. The interviewer's notes and struceured interview resus were reviewed by a commitce of J, AM, ACAD. CHILD ADOLESC. PSYCHIATRY, 55:6, AUGUST 1996 four boar-cerifed child and adult psychistrins chaired by the senior autor (J.B}. The commives was blind to the subjecs! ‘scertinment group, ascertainment sit, and al data collected rom thr family member, Diagnoses were considered postive f DSM- IER ester were unequivocally met. The committe members were aio made Bind to prior diagnoses ofthe same subject and thei family member Diagnoses presented For review were considered poise ony i 4 conennis wat achived that criteria were met to. degre tha would be considered cinially meaning By “linially ‘meaningl” we mean that the data collected from the severed Incerviw indiated thatthe diagno should be a clinical concern because ofthe nature ofthe sympeoms, the asocated impairment, and the coherence of che clinical picsure. Only the committe Approved diagnoses were used for the data anljes cepted in this are, “The dignoss of BPD was especially dependent on the emmit- tecsasessment. In making there diagnostic decons, the commit: tee rlerred to the coded diagnose tems fom che stuctced Iceni extensive margin aoter madeby theinteriewes inform tion about the persistence and consequences of the symptoms, sociated clinical ears, severity of mood instabliy, weatment history, and prior hospitalizations. Thus, che revuing diagnosis ves a clinical “best eximate” diagnos, nota simple enumeration of esitrn coded by the interviewer. ‘Ac baseline, 13 probands met criteria for BPD on the K-SADS- , butonly 9 (759%) of ths had BPD diagnosed by the commits 0F9 subjacs meeting subthreshold BPD criteria (ie, they met all exeria but one) at busine, 5 (55%) had BPD diagnosed by the committe on the basis ofthe atonal information described shove. At the 4-year fllon-up, 28 probands mec eriteria for BPD on the K-SADS-E but only 14 508) of ches had BPD diagnosed bythe commie OF6 subjects meting subthreshold BPD criteria 22 fllow-up, 1 (1798) had BPD dlagnosed by the commits on the bats of ational information. At both baseline and fellow up, the subjects not meeting criteria for either fll or subthreshold BPD wer all considered non-BPD by the commice, "To provide an additonal level of clinical validity for he bipole agnor, to bosr-cersied child and adolescent poychiatits reviewed the audiotaped interviews ofeach bipolar proband and examined medial records when these were available, The diagnosis SE BPD was rersined only i the paychierat agreed tac the abject, leary and unequivocally met exteria for mania based on this, ‘dditonal informacion To be given the lifetime diagnosis of mania, the child had wo sect fill DSM-ULR eer for a manic episode with associated imprrment. Thos, «child ma have met cteon A for period of exteme and pesinendy’ clevted, expansive or able mood, ples terion B, manifeced by dhe (Fur ifthe mood is ieeable ny) of seven symptoms during the peti of mood ditubance, pls ctterion C,asocatedimpaimene. Rapid cling was defined Shaving four of more episodes per year second othe operational .01; detailed information available on request) ‘Ar baseline, 15 ADHD children (11%) satisfied diagnostic criteria for BPD (baseline BPD). Fifteen new cases of mania out of 128 subjects available at follow-up (129%) developed at 4-year follow-up (F-U BPD) among ADHD children and 99 ADHD children did not have mania at either baseline or follow-up (non-BPD ADHD). Thus, a total of 30 of the 140 ADHD children (21%) had a lifetime history of BPD. ‘Compared with controls, ADHD children had higher rates of mania at both baseline (11% versus 0%, p< .001) and follow-up (12% versus 1.8%, p < .001), One of the 15 ADHD children with comorbid mania at baseline was lost to follow-up and 2 of the 109 normal controls developed mania at follow-up. Thus, comparisons were made between 107 normal controls and three groups of ADHD children: 14 with baseline BPD, 15 with F-U BPD, and 99 non-BPD ADHD children without mania at either baseline or follow-up. ‘The most common presentation of BPD at cither baseline or follow-up was mixed, with major depression and mania co-occurring simultaneously (x = 8, 579 and n = 7, 47% for baseline and follow-up bipolar groups, respectively). The least common was biphasic, with separate episodes of mania and major depress (n= 8, 57% and m = 7, 47% for baseline and follow- up bipolar groups, respectively). While baseline BPD 1000 children tended to have a simultaneous emergence of manic and depressive symptomatology, the majority of E-U BPD children manifested major depression fist (11% versus 70%, p = .01, depression onset first for baseline versus follow-up bipolar groups, respectively). ‘There were significant differences among the three ADHD groups and controls in socioeconomic status, intactness of the family, and family history of psychiat- ric disorders (Table 1). Both BPD groups had elevated rates of familial ADHD that did not differ from the rate of familial ADHD observed in non-BPD ADHD children. In contrast, familial BPD and familial major depression were markedly elevated in che BPD groups but not in the non-BPD ADHD group. The rates of familial anxiety were elevated in all three ADHD groups but were highest among the two BPD groups. Psychiatrie and Functional Outcomes There were striking similarities berween the two BPD groups in their elevated rates of severe major depression, multiple anxiety disorders, conduct disor- der, and oppositional defiant disorder, and in the mean number of comorbid disorders per child at both baseline and follow-up assessments compared with non-BPD ADHD probands. This was so despite the fact that F-U BPD probands did not have BPD at baseline. In addition, F-U BPD children, but not baseline BPD children, had an increased risk for substance use disor- der and psychosis ae follow-up compared with non- BPD ADHD children (Table 2). As depicted in Table 2, there were striking similarities between the baseline and follow-up bipolar groups for concurrent psychiatric correlates, as wel. Figure 1 displays CBCL findings at the baseline and Acyear follow-up assessments. Although they did not always reach statistical significance, the following findings are noteworthy: (1) CBCL clinical scales were much worse in baseline and F-U BPD children com- pated with non-BPD ADHD children; (2) mean CBCL scale scores were relatively stable over time in both BPD groups; (3) F-U BPD children had similarly abnormal CBCL scales before and after the onset of mania; and (4) ADHD children with and without comorbid BPD had similar elevations in the Attention Problems scale, which indexed ADHD symptoms, but BPD children had marked differences in anxiety/de- pression, delinquency, and aggression before and after the development of mania. J. AM, ACAD, CHILD ADOLESC, PSYCHIATRY, 35:6, AUGUST 1996ADHD AND COMORBID MANIA IN A LONGITUDINAL STUDY TABLE 1 Sociodemographic and Clinical Charcternics of Sample ‘ADHD Probands eae Busine BPD Followup BPD Non-BPD Normal Controls Significance Ged) 5) (= 99) (= 107) @-3) Sociodemographics ‘Age (eat) ‘Bascine 107 + 29 log + 32 ws+30 15 +36 183 Follow-up 146 * 29 6 #34 W331 © 152 437 354 Socioeconomic satus at basline ane 22st 17 t0s" 15 £07 01 Parents divored or ‘separated at baseline ) sme 3 2 18 08 Psychic family history (96) Bipolar disorder aot 20 7 7 018 Major depresion sre sae Py 19 01 Avwiety disorder mu Got 4st 32 ‘04 ‘ADHD 23 a 40 0 01 "Note: ADHD = aention-dfict hyperactivity disorder, BPD, = bipolar dorder. “p-s.01,” p S05 verus ADHD probands without BPD; *p $01, © p $05 versus control probands by Pearson 1 analysis (df= 1), Nonparametric tes were used for ordinal data and when variances Analyses of individual symptoms showed that ADHD children satisfying criteria for BPD at baseline and follow-up assessments had prominent prototypical symptoms of mania, with severe agitation and itrtabil- ity rather than euphoria dominating the clinical picture (Fig. 2). In addition, they also had the prototypical symptoms of ADHD. At baseline, the number of ADHD symptoms did not differ significantly among, the baseline BPD (10.6 + 4.7), F-U BPD (123 + 1.6), and non-BPD (10.7 + 3.2) ADHD children. At follow-up, the number of ADHD symptoms also did not differ significantly among groups (baseline BPD: 8.4 = 4.8; F-U BPD: 10.5 + 3.8; non-BPD: 7.9 + 3.8). Examination of the clinical features of manic children with ADHD revealed that BPD tended to have its onset in childhood (mean age 5 for baseline BPD and 11 for F-U BPD), to have multiple episodes (mean of 19 for baseline BPD and 7 for F-U BPD), and to have many symptoms (mean of 6 for both groups). Significant differences among the groups were also found in all cognitive and functional variables assessed. (Table 3). These were more impaired in the three ADHD groups irrespective of comorbid BPD status. Both groups of BPD children had markedly more impaired scores on the global assessment of functioning than did other ADHD children, and both had a significantly higher rate of placement in special classes J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 35:8, AUGUST 1996 ‘were not equal at both baseline and follow-up assessments. Significant differences among the groups were also observed in history of psychiatric hospitalization, accounted for by higher rates in che ewo BPD groups than in non-BPD ADHD children (Table 3). ‘Symptom Overlap Analyses Of seven DSM-IILR criteria for a manic episode, three are shared with the DSM-IILR criteria for ADHD: distractibility, mororic hyperactivity, and talk- ativeness. To avoid counting symptoms twice toward the diagnosis of both ADHD and mania, we reassessed each individual by using ewo differene techniques chat corrected for the overlapping diagnostic criteria. We did not adjust for items that were criteria for one disorder that might be considered an “associated fea- ture” of the other (e.g., decreased need for sleep). The symptom “fidgery” was used as the index of motor hyperactivity for the ADHD diagnosis. ‘The first approach, which we refer to as the subtrac- tion method, involved subtracting the overlapping. sympcoms and applying the same criteria required in DSM-II-R. However, the subtraction method is overly stringent because the exclusion of overlapping symp- toms reduces the number of possible symptoms that can be endorsed. To adjust for this stringency, the diagnosis of ADHD was reevaluated using a second 1001BIEDERMAN ET AL. TABLE 2 Paxcen of Paychiatric Comorbidity a Baseline and 4Year Followaup [ADHD Probands ae Bascine BPD Follow-up BPD Non-BPD Normal Controls Significance Ge) Gee 15) (n= 99) 107) 3) Major depression ievere) (8) Baseline oat 33 23 2 on Followup 93 me Ba ‘ ‘01 Maile (22) aiey disorders (8) Baseline sot a3 23 5 001 Follow-up one ane 25 3 01 Conduct disorder (96) ‘Baseline srt sas ne a 01 Follow-up nee one 16" 5 001 Oppositional defiant disorder (9) Baseline gat sot sot 8 01 Follow-up 93 too * wot 5 01 Paychoactve substance use disorder (06) Baseline 7 ° 2 6 re Follow-up 4 soe n 5 035 Prychoss (98) ‘Bascine ° ° ° 1 753 Follow-up Zi Be 3 1 047 No. of comorbid disorders* Baseline a8 togrt 3241384 23212 03 £07 ‘01 Follow-up ome 37 Euis* 24-512 oF B10 01 "Now: ADHD = random deck Iypanaviy doles BPD © IIT. p05 vera ADD bend ithe BPD: bipolar disorder %p <.01 versus control probands by Pearson x? analysis (df= 1). Nonparametric tess were used for ordinal daca and when variances were not equal “ADHD and BPD were included in the total number of prychiatic disorder, technique which we call the proportion method. This approach required that the observed proportion of symptoms in the reduced set of symptoms be at least as large as the proportion of symptoms required by the original criteria (Milberger et al., 1995). For example, DSM-ILR requires 8 (57%) of 14 symptoms for the diagnosis of ADHD. Using the proportion method, ‘we discard three symptoms from the criterion set and are lefe with 11 diagnostic criteria Fifty-seven percent of 11 is 6.3. Thus, the proportion method requires that 6 of 11 symptoms are present to diagnose ADHD. Fifty percent (n= 7) ofthe 14 baseline BPD children continued to meet criteria for mania by the subtraction method and 79% (n= 11) by the proportion method of overlapping symptom correction. Forty-seven pet- cent (n = 7) of the F-U BPD children maintained the 1osis of BPD by the subtraction method and 60% (n= 9) by the proportion method. Eighty-six percent 1002 (n= 12) of the baseline BPD children maintained a full diagnosis of ADHD by the subtraction method and 93% (n= 13) maintained the diagnosis by the proportion method after correcting for the three over- lapping diagnostic criteria. Ninety-three percent ( 14) of the F-U BPD children maintained the ADHD diagnosis by both the subtraction and proportion methods. DISCUSSION ur systematic evaluation of structured interview derived data from a sample of ADHD children showed that (1) a clinical picture compatible with the diagnosis of BPD was identified in 11% of ADHD children at baseline and in an additional 12% at 4-year follow- up by midadolescence, rates that were significantly higher than chose of concrols at each assessment; (2) J. AM, ACAD. CHILD ADOLESC, PSYCHIATRY, 35:8, AUGUST 1996ADHD AND COMORBID MANIA IN A LONGITUDINAL STUDY the clinical picture of mania in these ADHD children was predominantly irritable, and mixed with rapid cycles and increased activity, (3) compared with other ADHD children, those wich comorbid BPD at either baseline or follow-up had significantly higher rates of major depression, conduct disorder, oppositional defiant disorder, anxiety disorders, psychiatric hospital- ization, and severely impaired psychosocial functioning, findings previously associaced with juvenile mania (Woaniak et al., 19952); (4) ADHD children with comorbid BPD had a very severe symptomatic picture of ADHD and prototypical correlates of ADHD; (5) comorbidity between ADHD and BPD was not due to diagnostic criteria shared by the two disorders. These findings suggest that BPD may represent a serious comorbidity of ADHD that deserves careful clinical and scientific attention, The 23% rate of BPD in our sample of pediatrcally and psychiatrically referred ADHD children and adoles- cents is consistent with the 16% rate of mania we found in a separate sample of preadolescent psychiatrically referred children (Wozniak et al., 1995a), the 22% rate of mania reported by Weller et al. (1986) among, severely disturbed children, and a 22% rate among hospitalized ADHD children recently reported by But- ler et al. (1995). Taken cogether, these findings not only challenge the commonly held notion that mania is rare or nonexistent in children but also document that BPD is overrepresented in ADHD children and adolescents ‘Our finding that mania may be an important comor- bidity of ADHD supports previous studies of juvenile mania (Potter, 1983; Poznanski et al., 1984), studies of childhood histories of bipolar adults (Sachs et al. Baseline CBCL Scores Mean T-Score ‘Withdrawn (1) Somatization’ Anxious/ "Social Thought "Attention " Delinquent " Aggressive Depressed (1) Problems (1) Problems (1) Problems (1) Behavior (1) Behavior (1) Fig. 1. Child Behavior Checks (CECL) score for the Bazine BPD group (blk fez), followup BPD group (white boxe), non-BPD ADHD group (Bek cre), and normal contol whit cre). 7p < 01, "p< 05 vee non-BPD group #p <05 venue fllowup BPD groups (1) p<.01 veut controls forall ADHD group. BPD = bipolar dard, ADHD « atenson-defie hyperactiy disorder, J. AM, ACAD. CHILD ADOLESC. PSYCHIATRY, 25:8, AUGUST 1996 1003,BIEDERMAN ET AL. 1993; Winokur et al, 1993), and high-risk studies of children of bipolar parents (Grigoroiu-Serbanescu et al,, 1989; Kestenbaum, 1979). For example, West et al. (1995) found that 57% of adolescent bipolar patients met criteria for ADHD. Winokur etal. (1993) showed that bipolar adults and their adult bipolar relatives were more likely to have had a childhood history of hyperactivity compared with findings in unipolar subjects. Sachs et al. (1993) found comorbi ADHD exclusively among early-onset (before age 18) bipolar adults. ‘The significandy elevated rates of major depression, psychosis, and psychiatric hospitalization as well as the higher familiaicy of mania and major depression in ADHD+BPD children compared with other ADHD children support the validity of the mania diagnoses. ‘Similarly, the patterns of familiality of ADHD, cogni- tive deficits, and school failure identified in ADHD children with comorbid BPD are consistent with findings in ADHD children without mania in this study as well as with findings reported in other samples of ADHD children reviewed elsewhere (Faraone and Biederman, 1994a,b; Faraone et al, 1993; Semrud- Clikeman et al, 1992). That ADHD children with comorbid BPD show the psychopathological, cognitive, and familial features of both disorders suggests that both disorders had been validly diagnosed. (Our CBCL findings are consistent with our previous work documenting CBCL scale elevations for Delin- quent Behavior, Aggressive Behavior, Somatic Com- plaints, Anxious/Depressed, and Thought Problems in a sample of consecutively ascertained bipolar children i Bipolar Symptoms Percent Percent ae Cre at ° oe gs ao ae Fig.2_Frequeney of individual smprons in ADHD probands: Baseline BPD group (sek bux) followup BPD group (white bos), non-BPD ADHD 0p (black cna). BPD = bipaa disorder, ADHD = aention defi hypeacivy disorder, 1004 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 35:8, AUGUST 1996ADHD AND COMORBID MANIA IN A LONGITUDINAL STUDY TABLE 3 anetional Measures ADHD Probands pal Busine BPD Follow-up BPD NowBPD Normal Controls Significance G=14) (r= 15) (eo 99) (w= 107) (= 3) Eacmated Full Sale IQ Baseline 1078 +1134 1005 + u9* 1.4 + 1324 1183 + 190 01 Follow-up 1046 = 126" 106.1 = 117 1078 = 1426 L165 = 104 01 Global Assessment of Functioning Baseline gag saree 4632 61 499+ 68 700 1 Follow-up M2276 lz 80 551569" 672 = 01 Special class (%6) Baseline sme os 2 1 oan Follow-up nee oa 3a 2 ‘001 Paychiatic hospitalization* (%) Baseline ° ° 2 ° 428 Follow-up 2st 20 3 ° 01 ‘Note: ADHD = attention-defiie hyperactivity disorder; BPD = bipolar disordes *p $.01, * p $.05 versus ADHD probands without BPD; #p <.0 probands with onset of BPD at follow-up by Pearson ? analyst (df arias were not equal: " Paychiatic hospitalization was determined by parental report (Biederman et al., 1995). In the present sample, ADHD children with BPD tended to have higher CBCL scores than other ADHD children, especially for Delinquent Behavior, Aggressive Behavior, and Social Problems. Although there is no pathognomonic CBCL profile for BPD, itis reassuring that che dimensional approach. of the CBCL is consistent with the categorical struc- tured interview data in showing that ADHD with BPD is associated with more severe levels of psychopathology than are other cases of ADHD. ‘We found that the predominant mood in the chil- dren meeting criteria for mania was that of severe irritability rather than euphoria. This is consistent with other work documenting that manic episodes in young, children ate seldom characterized by euphoric mood (Carlson, 1983, 1984; Faedda et al., 1995). OF course, irritability isa common symptom in childhood psycho- pathology, and tantrums are common among children. ‘with ADHD. However, the type of irritability observed in ADHD children with mania was very severe and often associated with violence. This type of severe instability and “affective storms,” associated with pro- longed and nonpredatory aggressive outbursts (Davis, 1979), is precisely the one identified in the liverature dealing with childhood-onset mania. J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 35:8, AUGUST 1996 © p $.05 versus contol probands; “p <.01 versus ADHD ‘Nonparametric ests were used for ordinal data and when Our results also indicate that childhood-onset mania is commonly mixed, with symptoms of depression and mania occurring simultaneously, with rapid cycling. ‘These findings are consistent witha licerature suggesting that the earlier the onset of BPD, the greater the frequency of mixed states (Goodwin and Jamison, 1990; McElroy et al, 1992; Ryan and Puig-Antich, 1986). Given the possible continuity of BPD from childhood to adulthood, it is conceivable that child- hhood-onset mania increases the risk fora mixed disorder and perhaps rapid cycling throughout the life into adulthood. Our data on symptom expression for ADHD and ‘mania show that the comorbidity berween ADHD and ‘mania could not be accounted for by the diagnostic criteria shared by the two disorders (distractbi motoric hyperactivity, and talkativeness). The ability to retain diagnostic status for both mania and ADHD after removing overlapping diagnostic criteria supports the assertion that each diagnosis was made robustly, with more than the minimum criteria met Our data suggest that the subsequent development of mania in ADHD children may be predictable from certain clinical features. Notably, ADHD children who developed BPD at the 4-year follow-up had higher 1005,BIEDERMAN ET AL, initial rates of comorbidity, more symptoms of ADHD, worse scores on the CBCL, and a greater family history of bipolar and non-bipolar mood disorder compared with non-BPD ADHD children. If confirmed, these findings could provide a means for predicting the onset of bipolarity in ADHD children. Since ADHD and mania individually are associated with elevated morbidity and disability, their co-occur- rence may herald a severe clinical picture of high morbidity and perhaps mortality. For example, in one study, adolescents who completed suicide had signifi cantly higher rates of BPD, especially mixed subtype, and a higher rate of comorbid ADHD, than those who attempted suicide (Brent et al, 1988). Because ADHD compounds the impulsivity of a severe, mixed, manic state, the combination of ADHD and mania may be potentially lethal. ADHD children with comorbid BPD had a high degree of comorbidity with anxiety, conduct, and oppo- sitional disorders. These findings are consistent with previous reports in the literature. Carlson and Kashani (1988) found that nonreferred adolescents with manic symptoms had increased rates of anxiety and disruptive disorders. Bashir et al. (1987) noted that anxiety disor- ders were present in 53% of 30 adolescents with mania or hypomania. Similarly, Zahn-Waxler et al. (1988) and Sachs et al. (1993) both reported an. increased risk for anxiety in high-risk children of bipolar parents The Epidemiologic Catchment Area data show that, even in nonreferred samples, a significant overlap exists between bipolar and panic disorders (Chen and Dil- saver, 1995). Similarly, Lewinsohn and coworkers’ (1995) epide- iological study of a representative community sample of 1,700 adolescents also found high raves of comor- bidity of BPD with anxiety and disruptive behavior disorders. In that study, even a subthreshold BPD diagnosis was associated with a chronic course, signifi cant functional impairment, high rates of suicide at- tempts, and high rates of mental health care utilization. ‘Taken together these findings highlight the large clinical and public health significance of even the milder cases of juvenile BPD. Since juvenile mania has high levels of irtitablity that can be associated with violence and antisocial behavior (McElroy et al., 1992; Ryan and Puig-Antich, 1986), this overlap becween BPD and conduct disorder is not entirely surprising. Notably, Lewinsohn and 1006 coworkers’ (1995) epidemiological study found high rates of comorbidity between bipolar and disruptive behavior disorders. If this overlap continues to be confirmed, these findings may provide some new leads asto the possibility of subtypes of mood-based antisocial disorders not previously recognized. It is possible that previously reported findings documenting the beneficial effects of lithium (Lena, 1980) and carbamazepine (Campbell et al., 1992) in children with conduct disorder may be accounted for by those with BPD (Campbell et al., 1995). Although our data provide evidence for the validity of childhood mania in children with ADHD, they should be interpreted with caution. Although our BPD. children satisfied full diagnostic criteria for mania, it is very difficult to make bipolar diagnoses in children, especially in the context of comorbid ADHD. Noxably, the phenomenology of both disorders includes impul- sivity, overactivity, poor judgment, and irritability. Nevertheless, we have shown here, and in a different sample (Milberger et al.. 1995; Wozniak et al. 1995a), that these shared criteria cannot account for the ob- served comorbidity. Also, the presence of mixed symp- toms with major depression makes this clinical picture of BPD in children “atypical” by adult standards and contributes to the difficulry in distinguishing these children from those with ADHD. Thus, our work raises several nosological questions. Are children who meet criteria for mania severe cases of ADHD with affective dysregulation? If so, do they fall on a continuum of severity with other ADHD cases or do they constitute an etiologically or pathophys- iologically distinct subtype? Alternatively, are these children truly cases of BPD? If so, is their disorder nosologically distinct from classic BPD or do their atypical symptoms and course indicate a varying devel- ‘opmental expression of BPD? Despite the debate about what to call ADHD+BPD children, most clinicians would agree that these children exist and that they exhibita syndrome of severe, disabling psychopathology and mood dysregulation frequently leading to hospital- ization and marked impairment. Treatment, family, and follow-up studies are needed to clarify the nosologi- cal status of children who meet criteria for mania. Family-genetic data have been reported. Using famil- ial risk analysis, we have shown in two separate studies that relatives of ADHD children with and without BPD are at greater risk for ADHD compared with | AM. ACAD, CHILD ADOLESC. PSYCHIATRY, 35:8, AUGUST 1996ADHD AND COMORBID MANIA IN A LONGITUDINAL STUDY relatives of normal controls, but the risk for BPD was limited to relatives of ADHD with comorbid BPD (Faraone et al., unpublished; Wozniak et al., 1995b). ‘These findings plus those showing that ADHD and BPD cosegregated in families suggest that ADHD children with BPD are familialy distinct from other ADHD children and may have what others (Strober, 1992; Todd et al., 1993) have termed childhood onset BPD. Our findings should be evaluated in light of specific methodological limitations. Although reliability for the mood disorder modules of the K-SADS-E has been documented (Chambers et al., 1985), less is known about the validity of the modules. However, structured dliagnostic interview techniques can minimize mant and clinician bias (Robins, 1985). Given a reluc- tance t0 diagnose BPD in young subjects, structured interviews provide a means of identifying cases that might otherwise have been misattributed. Moreover, structured interview data were always reviewed by experienced, board-certified child and adolescent psy- chiatrists before final diagnostic assignment, thereby enhancing the credibility of the findings. A potential source of bias stems from the lack of direct interviews with children younger than 12 years. This may have Jed to.an underrepresentation of psychopathology, espe- cially for “internalizing” disorders such as anxiety and depression. Despite these limitations, our findings indicate that wich systematic assessment methodology, a dinical picture compatible with the diagnosis of childhood mania can be identified in ADHD children. This clinical picture compatible with the diagnosis of mania is characterized by severe irritability, a mixed presenta- tion with symptoms of depression and mania, and multiple episodes. 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(19852), Mantle ‘iggtve of chldhood-onet bipolar disorder in clinkally refered Chilien dm Aead Child Adoloe Pyciary 34:867-875 ‘Wounak J, Biedevman J, Muay E, Meanin D, Fare SV (19958), A file family say of chldhood-onse mani / Ar dead Child Adslae Phir 31577-1583 Zahn Waslet C, Mayfield A, Radke-Yarow M, McKew D, Cyeyn Ly Davenport ¥ (1988), A Fllow-up investigation of ofpeing of pens with bipolar disorder. Ave J Pcie 145:506-509 cal Call for ‘A new AACAP Paychotherapy Research Award ($5,000) will be given for an article in this Journal of a study that best advances our understanding of the essential elements of psy- chotherapy, encompassing theory and technique. Research developing the methodology for ‘measuring efficacy, specificity, and outcome Submissions particularly encouraged. 1008 J. AM, ACAD. CHILD ADOLESC. PSYCHIATRY, 55:6, AUGUST 1996