Measures of attention and hyperactivity symptoms in a high-risk sample of children of bipolar parents

Journal of Affective Disorders 67 (2001) 159–165 www.elsevier.com / locate / jad

Research report

Measures of attention and hyperactivity symptoms in a high-risk sample of children of bipolar parents a

b

a

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Anne Duffy , Paul Grof , Stanley Kutcher , Carrie Robertson , Martin Alda

a,b ,

*

a

Dalhousie University, Department of Psychiatry, Halifax, Nova Scotia, Canada b University of Ottawa, Department of Psychiatry, Ottawa, Ontario, Canada c Royal Ottawa Hospital, Affective Disorders Service, Ottawa, Ontario, Canada Received 24 July 2000; accepted 4 June 2001

Abstract Background: To determine whether significant symptoms of inattention were present among the offspring of wellcharacterized bipolar parents. Methods: We included 53 offspring of 30 parents meeting DSM-IV criteria for bipolar disorder diagnosed by consensus on the basis of a SADS-L interview and a wealth of longitudinal clinical data. The unaffected parent had no lifetime history of a major psychiatric illness. Offspring, prospectively followed for up to 5 years, completed psychometric measures of attention and mood when judged to be at a good level of functioning (well, remitted or treated). Results: Those offspring with any lifetime psychiatric diagnosis endorsed more subjective problems with attention. However, there was no measurable difference on tasks of sustained attention between those with and those without a lifetime psychiatric illness including affective disorder. There was a significant association between self-reported symptoms of depression and inattention, but no association between either self-report measure and an objective measure of sustained attention. Limitations: This study was not intended to be a comprehensive neuropsychological investigation of at risk offspring. Conclusions: In this high-risk population, subjective difficulty with attention appeared to be state-dependent, associated with the degree of subjective distress related to an underlying psychiatric illness.  2001 Elsevier Science B.V. All rights reserved. Keywords: Bipolar disorder; Early onset; Adolescence; ADHD; Comorbidity

1. Introduction

*Corresponding author. Department of Psychiatry, Dalhousie University, Abbie J. Lane Building, 5909 Jubilee Road, Halifax, Nova Scotia, B3H 2E2, Canada. Tel.: 1 1-902-473-2712; fax: 1 1-902-473-1583. E-mail address: [email protected] (M. Alda).

Bipolar spectrum disorders are being diagnosed with increasing frequency among children and adolescents. The prevailing view is that these early onset presentations are often atypical in comparison to adult onset bipolar disorders in a number of aspects including a high rate of comorbidity (Geller and

0165-0327 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 01 )00391-3

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Luby, 1997; Kovacs and Pollock, 1995). One frequently reported finding is an association between early onset bipolar disorder and attention deficit hyperactivity disorder (ADHD). In clinical samples, children with ADHD are reported to have an increased risk of comorbid bipolar disorder (Biederman et al., 1996a,b). Similarly, very high rates of comorbid ADHD have been reported in samples of bipolar children (Geller et al., 1995; Wozniak et al., 1995a; West et al., 1995). Furthermore, elevated rates of ADHD have been reported in some (Chang et al., 2000; Carlson and Weintraub, 1993; Gershon et al., 1985; Grigoroiu-Serbanescu et al., 1989) but not other bipolar high-risk cohorts (Duffy et al., 1998; Hammen et al., 1990; Akiskal et al., 1985; Klein et al., 1985; Laroche et al., 1985). The nature of the observed association between ADHD and early onset bipolar disorder is unclear. True comorbidity between ADHD and bipolar disorder, defined as the occurrence of two separate illnesses, is to date not proven (Carlson, 1995; Kutcher, 2000). As discussed by Angold and Costello (1993), in order to determine if two conditions are actually co-occurring we must be able to clearly identify and describe each condition, on the basis of family history, etiology, course, treatment and response. This is especially challenging in pediatric populations given that the natural course of psychiatric illnesses are not well-characterized in children, alongside the observation that the course of these illnesses may change over time and development. Additionally, observed ‘comorbidity’ may to some degree be artefactual, representing a number of methodological biases including: clinician bias (tendency to look for a second condition given the presence of a first condition), overlapping symptoms between conditions, use of multiple informants (describing the same symptoms in different terms) and the nosological system in use (DSM selects for layering of diagnoses). The existing studies describing an association between ADHD and early onset bipolar disorder do not disentangle comorbidity in the true sense from methodological and artefactual effects as described above. As discussed by Klein et al. (1998), the validity of the bipolar diagnosis described in prepubescent patient samples remains to be proven;

especially given that these children suffer from chronic rather than episodic illnesses, and mood episodes are characterized by irritability rather than euphoria or depression. As pointed out by Carlson (1995), in her experience endorsement of manic symptoms represented a nonspecific index of the severity of underlying psychopathology rather than a specific indication of mania. With respect to the issue of overlapping symptoms, in one study the association between ADHD and bipolar disorder held up when overlapping symptoms were taken into account (Milberger et al., 1995). However, the validity of the comorbid conditions was not proven along other lines of evidence (i.e. course, treatment response, etc.). In some family studies, ADHD was elevated in the family members of bipolar probands (Wozniak et al., 1995b; Faraone et al., 1997) however, bipolar disorder was not elevated in the family members of ADHD probands. Therefore, one cannot conclude that ADHD and bipolar disorder cosegregate (represent alternative manifestations of the same underlying illness). Furthermore, the observation that the majority of the bipolar probands had comorbid ADHD and that a significant proportion of the affected relatives also met criteria for both bipolar disorder and ADHD could be interpreted as reflecting a clinical bias (presence of the first illness increased the likelihood of diagnosing the second illness). Finally, as pointed out by Carlson (1995), comorbidity in their young mood disordered sample often obscured the identification of specific antecedents because it is difficult to know, for example, if early problems with attention and conduct predict the manifestation of a later mood disorder or the comorbid condition (i.e. substance abuse). In order to clarify the relationship between early problems with attention and early onset mood symptoms, clinical and high-risk samples will need to be systematically studied longitudinally into adulthood. It is important to note that prospective longitudinal follow-up studies of ADHD children have not found elevated rates of affective disorders in adulthood (Klein and Mannuzza, 1991; Mannuzza et al., 1993; Weiss et al., 1985). In our ongoing prospective longitudinal study of the adolescent offspring of well-characterized bipolar parents, we have not

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found an elevated risk of ADHD compared to population norms (Duffy et al., 1998). This finding agrees with other reports of no clinically significant attentional problems in an uncomplicated sample of euthymic bipolar youths (Robertson et al., 1999; submitted for publication) and a lack of ADHD symptoms in the premorbid school histories of adolescent onset bipolar patients (Quackenbush et al., 1996). Given the discrepancy in findings across studies, we sought to further investigate the possible relationship between children at risk for bipolar disorder (affected and so far unaffected) and significant symptoms of inattention. By starting with a carefully diagnosed and longitudinally followed cohort of bipolar parents, with the other parent well, heterogeneity was reduced. In order to separate state from trait changes, offspring with a lifetime psychiatric illness were followed up and tested only when judged to be at a good level of functioning (remitted or treated).

2. Methods

2.1. Parent probands The parent probands represented a series of patients followed longitudinally by our group for up to 30 years in an affective disorders specialty clinic. All probands were interviewed according to SADS-L format by a pair of research psychiatrists and met both RDC and DSM-IV criteria for bipolar I disorder. The parents were classified based on their response to long-term lithium prophylaxis as described elsewhere (Grof et al., 1994). There were seventeen excellent responders (LiR) and ten clearcut non-responders (LiNR). As well, in three cases we included a bipolar first-degree relative of an excellent lithium responder. Final diagnosis and lithium response were determined by at least two additional psychiatrists on blind consensus review using all available interview and clinical data. In all cases, the other parent had no lifetime history of a major psychiatric illness (recurrent major depression, bipolar disorder, schizophrenia, schizoaffective illness).

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2.2. Offspring All male and female offspring between the ages of 10 and 25 years of eligible families (as described above) were approached for participation in the highrisk study. All consenting offspring were interviewed blind to family affiliation by the main author according to K-SADS format. In addition, at least one parent was interviewed about each child. Final DSMIV diagnoses were determined by blind consensus review between the co-authors. There was only one occasion of disagreement in diagnosis. This offspring was reinterviewed by a different research clinician and represented blindly to the panel and a consensus was reached. As part of the high-risk study, consenting offspring were reassessed according to the described research protocol a number of times over a 5-year period. In this paper, we are reporting on 53 offspring (31 females and 22 males) from 30 families who completed one or both ADHD psychometric measures. The mean age at the time of assessment was 17.264.61 years (range 10–27 years). Twenty-four of the fifty-three offspring met DSM-IV criteria for at least one lifetime psychiatric diagnosis, mostly in the mood and / or anxiety disorder spectrum (see Table 1).

Table 1 DSM-IV lifetime psychiatric disorders among the children of bipolar parents Diagnosis

Na

Bipolar I disorder Bipolar II disorder Bipolar disorder not otherwise specified Schizoaffective disorder Cyclothymic disorder Major depressive disorder Minor depressive disorder Anxiety disorder Adjustment disorder Substance use disorder Sleep disorder Cluster A personality disorder Attention deficit disorder Learning disability No diagnosis

1 1 2 1 1 9 2 7 1 4 2 2 1 2 29

a

Some individuals met lifetime diagnostic criteria for more than one disorder.

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2.3. Measures of attention

determine the degree of association between continuous measures.

All consenting offspring were asked to complete the Talland Letter Cancellation Test (Talland, 1965) and the ADHD Symptom Rating Scale (ADHDRS) (DuPaul, 1991) at a good level of functioning; that is, at the time of assessment for well offspring and after remission or treatment stabilization for psychiatrically ill offspring. The Letter Cancellation Test requires visual selective attention at a fast speed (scanning for a target stimulus) and a repetitive motor response (crossing out). The test measures multiple functions including sustained attention and divided attention requiring the subject to focus on a target while actively ignoring distractions (Lezak, 1995). The number of missed targets (omissions) and the number of incorrectly crossed out targets (commissions) were averaged across two trials for each of three separate tasks. The ADHDRS was used as a self-report measure in the study. Offspring were asked to rate themselves on a 5-point scale (‘never’ to ‘continuously’) on ADHD symptoms developed from the DSM-III-R diagnostic criteria. The ADHDRS is a measure of ADHD symptoms that has been employed in clinical populations (Kutcher, 1997). At the time of completion of attention measures, all children filled out the Beck Depression Inventory (BDI) (Beck et al., 1961).

2.4. Statistical analysis Total percentage error scores (T1–T3) on the Letter Cancellation Test were calculated for each of three tasks (number of omissions 1 number of commissions) / number of correct responses. Nonparametric methods were used to analyze the data. For between-group comparisons, we used the Mann– Whitney test. Spearman rank correlation was used to

3. Results All analyses were performed initially comparing between children of LiR and children of LiNR. There were no differences between these high-risk groups so the data were pooled.

3.1. ADHDRS There was a significant difference in ADHDRS total scores between psychiatrically well and psychiatrically ill offspring (P 5 0.008). There was also a significant difference in total scores between those with and those without an affective disorder in particular (P 5 0.006). In summary, those offspring with a lifetime psychiatric diagnosis tended to report more difficulty with attention and / or hyperactivity symptoms despite being at a good level of functioning (Table 2). Spearman Rank correlational analysis revealed a highly significant association between total scores on the ADHDSRS and the BDI (r 5 0.63; P , 0.001) (Fig. 1). However, there was no significant association between either of these self-report measures and the cancellation test total percentage error scores on each of three tasks: ADHDRS vs. T1–T3 (r 5 0.037, r 5 0.019, r 5 2 0.102) and BDI vs. T1–T3 (r 5 0.081, r 5 2 0.021, r 5 2 0.190).

3.2. Letter cancellation test There was no effect of having a lifetime psychiatric diagnosis or an affective disorder in particular on the total percentage error scores across three tasks. In other words, those with a lifetime psychiatric diag-

Table 2 Self report measures — mean total scores Any psychiatric disorder

ADHDSRS BDI

Affective Disorder

Yes n 5 24

No n 5 29

Yes n 5 17

No n 5 36

42.5 (8.2) 7.3 (9.3)

35.9 (9.2) 2.4 (3.4)

43.8 (8.2) 8.7 (10.4)

36.6 (9.0) 2.7 (3.7)

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Fig. 1. Beck Depression Rating Scale.

nosis at a good level of functioning did equally as well as those without a psychiatric disorder on an objective measure of attention (Table 3).

4. Discussion The main finding of this study was a lack of objective evidence of significant symptoms of inattention between the well compared to the psychiatrically remitted or stabilized offspring of well-characterized bipolar parents. This is in agreement with our earlier report of no elevated rate of diagnosable ADHD among this at risk cohort (Duffy et al., 1998). Further, these findings agree with our observation of good premorbid functioning in the majority of offspring of LiR who later developed a mood disorder (Duffy et al., 1999). While not a direct test of the association between early onset bipolar disorder and ADHD, this study supports the finding of other studies suggesting that ADHD as a Table 3 Letter cancellation test — percentage total error scores

Task 1 Task 2 Task 3

Psychiatric diagnosis

Affective disorder

Yes n 5 21

No n 5 26

Yes n 5 15

No n 5 32

10.4 (19.0) 3.7 (4.2) 5.4 (7.1)

12.2 (13.8) 7.6 (9.6) 9.3 (11.4)

12.5 (22.3) 4.0 (4.4) 5.8 (8.2)

10.9 (12.8) 6.7 (8.9) 8.4 (10.6)

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separate disorder is neither a true antecedent condition to nor a valid comorbid condition with early onset bipolar disorder. The discrepancy between our findings and those of some other groups may reflect the sample we are studying. We have started from a cohort of bipolar parents whom we have treated according to a research protocol and followed prospectively for many years (Grof et al., 1994). These parent probands have comorbid psychiatric illnesses only as often as expected in the general population. As well, the other parent had no lifetime history of a major psychiatric illness in all cases. Therefore, their offspring represent an uncomplicated group of adolescents at risk for bipolar disorder. Further, response to long-term lithium monotherapy did not affect the likelihood of subjective or objective problems with attention and / or restlessness. As reported elsewhere (Alda, 1997), an excellent response to long-term lithium monotherapy appears to be a valid clinical marker of a genetically based subgroup of bipolar patients. The lack of association with ADHD across lithium responsive subgroups in this study (homogeneous vs. heterogeneous) further supports the validity of the reported negative finding (no association between bipolar disorder and ADHD). By contrast, groups reporting high rates of comorbidity between ADHD and early onset bipolar disorder are typically reporting on prepubertal children. These children tend to exhibit non-classical symptomatology and often derive from genetically heterogeneous families. Taken together with the lack of prospective data on the course of very early onset psychiatric illnesses, we agree with Klein et al. (1998), that the validity of the bipolar–ADHD diagnosis in these prepubertal children needs further study. It would have strengthened our findings if we had included a number of different measures of attention in the assessment. However, our focus was the prospective characterization of the early course of bipolar illness and, therefore, a systematic neuropsychological assessment was not undertaken. Another limitation is the fact that we studied a sample of youths at risk for bipolar disorder and thus this is not a direct test of the association of ADHD and early onset bipolar disorder. The significant association between subjective

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ratings of inattention and depressive symptoms together with the lack of association between these measures and an objective measure of attention suggests to us that subjective attentional difficulties reflect the activity of the underlying primary psychiatric illness. In other words, those youths experiencing more psychiatric symptoms also endorsed more symptoms of inattention despite no measurable difficulty with sustained attention and no premorbid history of ADHD. This finding cautions against the overdiagnosis of ADHD in the presence of another Axis I disorder. In order to be truly comorbid, ADHD would have to be present during early childhood (likely prior to the manifestation of the other Axis I disorder), during remissions of the concurrent illness and require specific treatment (not subside with stabilization of the other illness). From our findings, it appears that subjective ADHD symptoms were not independent of, but rather intertwined with the course of the underlying major psychiatric illness.

Acknowledgements This study was funded by operating grants from the Ontario Mental Health Foundation, the Canadian Psychiatric Research Foundation (CPRF) and the Medical Research Council of Canada. Anne Duffy is supported by a Marcia Simon Young Investigator Award from NARSAD, while Martin Alda has been supported by an Independent Investigator Award from NARSAD.

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