Attention deficit hyperactivity disorder with bipolar disorder in girls: further evidence for a familial subtype?

Journal of Affective Disorders 64 (2001) 19–26 www.elsevier.com / locate / jad

Research report

Attention deficit hyperactivity disorder with bipolar disorder in girls: further evidence for a familial subtype? Stephen V. Faraone

a,b,c ,

*, Joseph Biederman a,b , Michael C. Monuteaux a,d

a

Pediatric Psychopharmacology Unit, Psychiatry Service, ACC 725, Massachusetts General Hospital, Fruit Street, Boston, MA 02114, USA b Department of Psychiatry, Harvard Medical School, Boston, MA, USA c Harvard Institute of Psychiatric Epidemiology and Genetics, Department of Psychiatry, Harvard Medical School at Brockton–West Roxbury Veterans Affairs Medical Center and Massachusetts Health Center, Boston, MA, USA d Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Received 11 June 1999; accepted 29 February 2000

Abstract Background: To clarify the nosologic status of girls with attention deficit hyperactivity disorder (ADHD) who also satisfy diagnostic criteria for bipolar disorder (BPD). Methods: Using blind raters and structured psychiatric interviews, we examined 140 girls with ADHD, 122 non-ADHD comparisons and their 786 first degree relatives. Analyses tested specific hypotheses about the familial relationship between ADHD and bipolar disorder in girls. Results: After stratifying our ADHD sample into those with and without BPD, we found that: (1) relatives of both ADHD subgroups were at significantly greater risk for ADHD than relatives of non-ADHD controls, (2) the two subgroups did not significantly differ in their relatives’ risk for ADHD; (3) an elevated risk for bipolar disorder was observed among relatives when the proband child had BPD but not ADHD alone; (4) weak evidence of cosegregation between ADHD and BPD, and (5) no evidence of a trend for random mating between ADHD parents and those with mania. Limitations: Limitations of this study include the lack of direct interviewing of probands and the limited number of ADHD/ BPD probands available. Conclusions: These findings extend to girls what was previously documented in boys and suggest that comorbid ADHD with BPD in girls is familially distinct from other forms of ADHD and may be related to what others have termed childhood onset BPD. Future work could determine if this subgroup has a characteristic course, outcome and response to treatment.  2001 Elsevier Science B.V. All rights reserved. Keywords: ADHD; Bipolar disorder; Genetics; Comorbidity; Nosology

1. Introduction *Corresponding author. Tel.: 1 1-617-726-1731; fax: 1 1-617724-1540. E-mail address: [email protected] (S.V. Faraone).

Prior work shows that the co-occurrence of ADHD and BPD is not a rare event. Systematic studies of children and adolescents show that rates of ADHD

0165-0327 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 00 )00213-5

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range from 57 to 98% in bipolar patients (Borchardt and Bernstein, 1995; Geller et al., 1995; West et al., 1995; Wozniak et al., 1995a) and rates of bipolar disorder range from 11 to 22% in ADHD patients (Butler et al., 1995; Biederman et al., 1996b). Despite these findings, little is known about the clinical and nosologic validity of bipolar disorder when it occurs in the context of ADHD — a condition that we will refer to as ADHD 1 BPD. One method of addressing nosologic validity is to examine the transmission of comorbid disorders in families (Faraone and Tsuang, 1995; Faraone et al., 1999). We reasoned that if ADHD and BPD were associated due to shared familial etiologic factors, then family studies should find BPD in families of ADHD patients and ADHD in families of BPD patients. We recently reviewed the literature for family studies that assessed both ADHD and BPD (Faraone et al., 1997a). Our meta-analysis showed that studies of ADHD (among the children of bipolar patients) found higher rates of ADHD among these children compared with controls. We also completed a metaanalysis of studies of relatives of ADHD probands. Taken together, these studies support the idea that the relatives of ADHD children are at increased risk for bipolar disorder. We began to systematically address this issue with a sample of consecutively referred pre-adolescent children with BPD. These children had very high rates of ADHD, and their relatives were at high risk for ADHD, mania and the comorbid condition. Moreover, the pattern of transmission in families suggested that ADHD 1 BPD might be a familially distinct subtype of bipolar disorder (Wozniak et al., 1995b). Consistent with this hypothesis, we also described a three-generation pedigree ascertained through an adult patient who had both ADHD and bipolar disorder (Faraone et al., 1996). Members of this family suffered from both bipolar disorder and methylphenidate responsive ADHD. Finally, we explored the competing hypotheses of familial transmission proposed by Pauls et al. (1986) and Reich et al. (1979) using a sample of ADHD boys. Our results suggested that comorbid ADHD with BPD is familially distinct from other forms of ADHD. Since much of this work is based on families derived from male samples of ADHD patients, little

is known about the familial link between ADHD and BPD among relatives of female patients, which is critical to permit the generalizability of findings to girls. Thus, in contrast to our prior report examining a sample of ADHD boys and their families, the present work used a different, independent sample of ADHD girls and their first-degree relatives. We sought to further clarify the nosologic validity of ADHD 1 BPD by again testing the competing hypotheses of familial transmission proposed by Pauls et al. (1986)) and Reich et al. (1979).

2. Methods

2.1. Subjects We studied two groups of index females: 140 ADHD probands and 122 non-ADHD comparisons. These groups had 417 and 369 first-degree biological relatives, respectively, who provided data. All of the ADHD females met full DSM-III-R diagnostic criteria for ADHD at the time of the clinical referral; at the time of recruitment they all had active symptoms of the disorder. All subjects older than 18 gave written informed consent for participation. Parents gave written informed consent for participation of children under 18 and these children participated only if they assented to the study procedures. We identified psychiatrically referred females from lists of consecutive ADHD patients from the pediatric psychopharmacology clinic at the Massachusetts General Hospital (MGH). Pediatrically referred ADHD females were identified from lists of children having evidence of ADHD in the computerized medical record of a Health Maintenance Organization (HMO). Within each setting, we selected normal controls from lists of outpatients at pediatric medical clinics.

2.2. Procedures We used DSM-III-R-based structured interviews to diagnose subjects supplemented with questions that would allow us to make DSM-IV diagnoses. Psychiatric assessments of probands and their siblings were made with the Kiddie SADS-E (Epidemiologic Version) (Orvaschel, 1985). Diagnoses were based

S.V. Faraone et al. / Journal of Affective Disorders 64 (2001) 19 – 26

on independent interviews with the mothers and direct interviews with the child. Children younger than 12 years of age were not interviewed directly. Diagnostic assessments of parents were based on direct interviews with each parent using the Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al., 1990). Ninety-two percent of the control parents and 88% of the ADHD parents were directly interviewed (P . 0.05). We ascertained data on the remaining parents who were not interviewed directly through indirect interviews with the available parent from that family. To assess childhood diagnoses in the parents, we administered modules from the Kiddie-SADS-E covering childhood diagnoses. The interviewers were instructed to take extensive notes about symptoms that were reviewed by a committee of four board-certified child and adult psychiatrists. The raters and the committee were blind to the subjects’ ascertainment group and all data collected from other family members. Diagnoses were considered positive if DSM-III-R criteria were unequivocally met and if a consensus was achieved that criteria were met to a degree that would be considered clinically meaningful. By ‘clinically meaningful’ we mean that the data collected from the structured interview indicated that the diagnosis should be a clinical concern due to the nature of the symptoms, the associated impairment, and the coherence of the clinical picture. Raters were trained and supervised by board certified psychiatrists (including JB), and had Bachelor’s degrees in psychology. They underwent an extensive 6-month training process, including classroom instruction on diagnostic criteria and the interview itself. They also observed and coded study interviews conducted by senior raters. If at least three observed interviews corresponded exactly with senior staff interviews, trainees then conducted interviews with senior staff observing. Finally, when perfect agreement was obtained on at least three interviews, the training was completed. No specific data on inter-rater reliability is available. Kappa coefficients of agreement were computed between raters and three board-certified psychiatrists who listened to audiotaped interviews. Based on 173 interviews, the median kappa was 0.86, the kappa for ADHD was 0.99, and 0.94 for bipolar disorder. We

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assessed socio-economic status (SES) with the Hollingshead–Redlich scale (Hollingshead, 1975) and functioning with Global Assessment of Functioning scale.

2.3. Hypotheses to be tested 2.3.1. Hypothesis 1 Posits that ADHD and BPD are etiologically independent and co-occur due to chance. It predicts equally high rates of ADHD in relatives of the ADHD without BPD and ADHD 1 BPD children (compared with controls) but BPD should be increased only among relatives of ADHD 1 BPD children (compared with controls). Also, ADHD and BPD should not cosegregate in families of ADHD 1 BPD probands (i.e. the ADHD relatives should not be at increased risk for a BPD diagnosis).

2.3.2. Hypothesis 2 Is that ADHD 1 BPD is a distinct subtype or an entirely separate condition. It predicts high rates of ADHD in relatives of ADHD without BPD and ADHD 1 BPD children (compared with controls) but BPD should be increased only among relatives of ADHD 1 BPD children (compared with controls). This is the same pattern as Hypothesis 1. However, we should also find strong evidence for cosegregation: among relatives of ADHD 1 BPD children, the presence of one disorder should predict the presence of the other.

2.3.3. Hypothesis 3 Posits that ADHD and BPD are etiologically independent but co-occur due to nonrandom mating (i.e. the spouses of ADHD individuals have higher rates of BPD than spouses of non-ADHD individuals).

2.3.4. Hypothesis 4 States that ADHD 1 BPD requires more familially transmissible etiologic factors for its expression compared with ADHD without BPD. It predicts higher risks for ADHD and BPD among relatives of

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ADHD 1 BPD compared with relatives of ADHD without BPD probands.

3. Results

3.1. Clinical and demographic features 2.3.5. Hypothesis 5 States that ADHD children with and without BPD share common familial etiologic factors but differ due to environmental effects. We should then find similar rates of ADHD and BPD in the relatives of both subgroups.

2.3.6. Hypothesis 6 Posits that the BPD among ADHD children is secondary to ADHD. It predicts no increased risk for BPD in families of ADHD probands (compared with controls), although some increase in BPD might be found among the ADHD relatives of ADHD probands.

2.3.7. Hypothesis 7 Posits that the ADHD among BPD children is secondary to BPD. It predicts no familial transmission of ADHD in families of BPD probands (compared with controls), although some increase in ADHD might be found among the BPD relatives of ADHD 1 BPD probands.

2.4. Statistical analysis We adjusted our analyses for the non-independence of siblings by using the Huber (1967) formula as implemented in STATA (Stata Corporation, 1992). We used the following sequence of analysis. We first compared all relatives in our three groups across relevant demographic variables. We then used logistic regression to compare the groups on the prevalence and family history of the disorders of interest. When the three-group comparison was significant at the 0.01 level of significance, we followed it with pairwise comparisons between groups. These latter comparisons used the 0.01 level of statistical significance. All statistical tests were two-tailed. To test for assortative mating, we used the entire ADHD sample to determine if ADHD in one spouse was predictive of BPD in the other spouse.

The two ADHD proband groups and the control group were similar in terms of SES, intactness of family, gender, and age of relatives (Table 1). For the ADHD 1 BPD probands, the age at onset of ADHD (3.1 years) was significantly earlier than that for BPD (6.8 years; t 13 5 2 2.83, P 5 0.01). Nine ADHD probands had onset of ADHD prior to BPD, four had onset of ADHD in the same year as BPD, one had onset of BPD prior to ADHD and one had a missing age of onset of ADHD, while the age for BPD was 14. Fifteen (11%) of our ADHD probands met criteria for BPD. The 15 ADHD 1 BPD children had a mean of 5.6 bipolar symptoms, 12.4 ADHD symptoms and a mean age at bipolar onset of 6.8 years. Their mean number of manic episodes was 23.6, with a mean total duration of 2.7 years. Six of the ADHD 1 BPD probands met criteria for rapid cycling (four or more episodes per year according to the operational definition outlined by Goodwin and Jamison (1990). All subjects showed concurrent symptoms of mania and depression (mixed or dysphoric mania). Although all of the ADHD 1 BPD probands met criteria for lifetime diagnoses of both ADHD and bipolar disorder, fewer met criteria based on current symptoms i.e. those that were active during the past month (eight met criteria for BPD during the past month and 12 for ADHD).

3.2. Familial risk analyses Rates of ADHD were elevated among relatives of both types of ADHD probands as compared to relatives of controls, but BPD was elevated only among relatives of ADHD 1 BPD probands, as compared to relatives of controls (Table 2). A similar pattern was found in the risk for BPD without ADHD. The risk for any ADHD 1 BPD was greatest in the relatives of ADHD 1 BPD probands, but the difference was not statistically significant. Notably, ADHD without BPD was highest among relatives of ADHD probands without BPD. (Table 2). The mean number of subjects per family was low for each group (3.2, 3.0, and 3.0 for ADHD 1 BPD,

S.V. Faraone et al. / Journal of Affective Disorders 64 (2001) 19 – 26

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Table 1 Demographic features Proband diagnosis

No. of probands No. of relatives

a

Low SES family Parents separated or divorced % male relatives

Age Age Age Age

of proband range of relatives range

% of adolescent probands ( . 12) a

Control

ADHD with bipolar disorder

ADHD w / o bipolar disorder

15 48

125 369

P value

122 369

n

%

n

%

n

%

2 6 24

13 40 50

26 33 194

21 26 53

14 22 191

11 18 52

Mean

S.D.

Mean

S.D.

Mean

S.D.

12.7 7–17 31.6 6–57

3.6 – 15.4 –

11.7* 6–18 32.6 6–60

3.3 – 14.6 –

12.7 6–18 33.4 6–63

3.0 – 15.5 –

n

%

n

%

n

%

7

47

57

46

73

60

0.130 0.086 0.995

0.037 – 0.227 –

2 0.074

2

Hollingshead–Redlich Class $ 4; * P # 0.05 vs. controls by Pearson x or t-test.

Table 2 Bipolar disorder and ADHD among relatives of ADHD children Proband diagnosis

Control

ADHD with bipolar disorder

ADHD w / o bipolar disorder

No. of adults No. of adolescents No. of children Total

34 4 10 48

267 45 57 369

Relatives

n

%

n

%

Any ADHD Any BPD ADHD 1 BPD ADHD w / o BPD BPD w / o ADHD

10 a 6a 3 7 3

21 13 6 17 8

92 a 19 9 83 a 10

25 5 2 24 4

a

259 48 62 369 n 23 10 3 20 7

%

P value a

6 3 1 6 2

, 0.001 0.005 0.020 , 0.001 0.049

P # 0.01 vs. controls by logistic regression.

ADHD, and control, respectively); there were no very large families. In an analysis examining the number of probands having one or more relatives with each disorder, the pattern of results is similar to that in Table 2, although one comparison, any BPD, loses significance. These analyses control for family size because high-density families cannot bias them. Thus, we conclude that a few highly dense families

are not accounting for our results (detailed data available upon request). Our assessment of cosegregation showed that among the ten ADHD relatives of the ADHD 1 BPD probands, three (30%) had BPD. In contrast, three of the 38 (8%) non-ADHD relatives of the ADHD 1 BPD probands had BPD ( x 2 5 3.54, P 5 0.06). To test for non-random mating, we tested the association

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of ADHD and BPD between spouses. Among the 25 fathers with ADHD, one (4%) had a spouse with mania compared with six of 106 (5.7%) spouses of non-ADHD fathers ( x 2 5 0.1, P 5 0.74). Among the 34 mothers with ADHD, three (8.8%) had a spouse with mania compared with five of 100 (5%) spouses of non-ADHD mothers ( x 2 5 0.7, P 5 0.42).

4. Discussion In a new sample of families of ADHD girls, we found that: (1) relatives of both ADHD subgroups were at significantly greater risk for ADHD than relatives of non-ADHD controls; (2) the relatives in the two subgroups did not significantly differ from one another in their risk for ADHD; (3) a four-fold elevated risk for bipolar disorder was observed among relatives when the proband child had BPD as compared to relatives of controls, but not when the proband had ADHD alone; (4) we found weak evidence of cosegregation between ADHD and BPD; and (5) there was no evidence for a trend of random mating between ADHD parents and those with mania. These results are nearly identical to what we observed in a family study of ADHD boys, although in that study we found strong and significant evidence for cosegregation between ADHD and BPD. The pattern of familial transmission is partially consistent with hypothesis two. As that hypothesis predicted, most cases of BPD among relatives occurred among relatives of ADHD 1 BPD probands. But that hypothesis also predicts that, among relatives of ADHD 1 BPD probands, ADHD and bipolar disorder should co-occur in the same relatives more often than expected by chance alone. We did find that BPD was 3.8 times more common among the ADHD compared with the non-ADHD relatives, but the difference was only marginally significant (P 5 0.06), perhaps due to the small number of relatives in this subgroup (n 5 48). In contrast, in two prior studies, we observed statistically significant cosegregation between ADHD and bipolar disorder (Wozniak et al., 1995b; Faraone et al., 1997a). Our results reject hypotheses that assume all ADHD children have some familial risk for BPD. If that were true, then ADHD without BPD children

should have imparted some familial risk for BPD to their relatives. But that was not so: as we reported for the relatives of ADHD boys (Faraone et al., 1997a), the prevalence of BPD among relatives of ADHD girls was nearly the same as what we observed among control relatives. Our findings also reject hypotheses that attribute either disorder to be a secondary manifestation of the other (Hypotheses 6 and 7). These hypotheses were also rejected in our prior reports (Wozniak et al., 1995b; Faraone et al., 1997a). If ADHD 1 BPD was simply a severe form of ADHD, we should have found support for hypotheses 4 or 5. But hypothesis 4 predicted — incorrectly — that relatives of ADHD 1 BPD probands would be at higher risk for ADHD compared with relatives of ADHD without BPD probands. Moreover, our test of hypothesis 5 rejected a shared etiology model that attributed differences in severity between ADHD 1 BPD and ADHD without BPD to environmental factors. These findings are consistent with our prior studies, which also rejected these hypotheses (Wozniak et al., 1995b; Faraone et al., 1997a). In a sample of adults, Sachs et al. (1993) reported an association between childhood onset bipolar disorder and ADHD, suggesting that ADHD 1 BPD and childhood onset bipolar disorder may be the same disorder. Todd et al. (1993) proposed that childhood onset bipolar disorder might be a subform of BPD with a high familial loading. Notably, the 13% rate of BPD among relatives of ADHD 1 BPD probands was about twice as high as the mean risk to first degree relatives of 7% reported in the Tsuang and Faraone (1990) review of 17 family studies of adult bipolar probands. Thus, like childhood onset bipolar disorder, ADHD 1 BPD is highly familial. In summary, these converging findings suggest that further nosological work investigating the validity of a syndrome that exhibits childhood onset bipolar disorder, ADHD and high familial risks for ADHD and bipolar disorder be underaken. If the validity of this subtype is confirmed, it may be worthwhile for genetic studies to examine subforms of the disorder. Although our work provides support for the nosologic validity of ADHD 1 BPD, it would be premature to equate BPD with the typical adult form of bipolar disorder. The atypical picture of the

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ADHD 1 BPD children may indicate that they will grow up to become atypical bipolar adults. Indeed, their mixed presentation, chronicity and rapid cycling suggests that they may become the adults described by McElroy et al. (1992) as having dysphoric or mixed mania. Ideally, a long-term follow-up study of these children would clarify the nature of their disorder. As we have described elsewhere (Wozniak et al., 1995a; Biederman et al., 1996a,b; Faraone et al., 1997b), the predominant mood in bipolar children is severe irritability rather than euphoria. This is consistent with other work documenting that manic episodes in young children are seldom characterized by euphoric mood (Carlson, 1983, 1984). Of course, irritability is a common symptom in childhood psychopathology, and tantrums are common among children with ADHD. However, the type of irritability observed in our children with mania-like symptoms was very severe and often associated with violence. Many of these bipolar children are described as assaultive when irritable. The irritability in these children rapidly became violent, resulting in throwing and breaking things, kicking down doors and destroying property. This type of severe irritability and ‘affective storms’, associated with prolonged and nonpredatory aggressive outbursts has previously been identified in the literature dealing with juvenile mania (Davis, 1979). In our experience, severe irritability was the most common reason for these children to be psychiatrically hospitalized.

5. Limitations Our results should be evaluated in light of methodological limitations. Of the 15 ADHD 1 BPD probands, ten had only a parent interview and five were directly interviewed. Our diagnostic procedures would have benefited from clinician interviews with young children along with teacher reports. This is especially true for children who were symptomatic at the time of the interview. We did not assess for post-traumatic stress disorder (PTSD), which often is expressed with symptoms of ADHD and bipolarity. Thus, we cannot determine if cases of PTSD may have obscured our

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results. Yet, it seems unlikely that comorbid PTSD would mimic the pattern of familial aggregation that we observed. Although the number of ADHD probands without BPD was large (n 5 125), we only had 15 probands who met criteria for both ADHD and BPD. Thus, future studies would benefit from recruiting a larger subsample of ADHD 1 BPD children. Despite these limitations, our data when viewed in the light of prior research supports the hypothesis that the comorbid presentation of ADHD with BPD may be nosologically discrete from other cases of ADHD. The consistency of these findings with our prior reports suggests that further work should examine the clinical and research implications of the comorbid presentation of ADHD with BPD. Although there is much debate about what to call ADHD 1 BPD children, most clinicians would agree that these children exist and that they exhibit a syndrome of severe, disabling psychopathology and mood dysregulation frequently leading to hospitalization and marked impairment. Our finding that this subgroup has a distinctive pattern of familial transmission suggests that future work could determine if they also have a characteristic course, outcome and response to treatment.

Acknowledgements This work was supported in part by grant RO1 MH41314-07 from the National Institute of Mental Health and funds from the Commonwealth Research Center of Massachusetts (Dr Biederman).

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