This debate between Dr. Joe Biederman at Harvard and Drs. Klein, et al., was in the October, 1998, issue of the Journal of the American Academy of Child & Adolescent Psychiatry, and is posted here by permission of the Academy.
Series Editor: Lenore C. M.D.
Resolved [for debate]: Mania Is Mistaken for ADHD in Prepubertal Children
AFFIRMATIVE: JOSEPH BIEDERMAN, M.D.
As a child psychiatrist I have, for many years, faced the diagnostic conundrum and therapeutic complexities of juvenile bipolar disorder (BPD). Although considered rare in children, BPD is one of the most impairing forms of child psychopathology. In our region it accounts for most hospital admissions and emergency calls and is a major source of distress for the affected children and their family members. However, its diagnosis has been controversial because of diagnostic uncertainties, especially its symptomatic overlap with attention-deficit hyperactivity disorder (ADHD).
That children with BPD are diagnostically challenging has long been recognized. For example, Carlson reported that children with BPD were severely irritable, dysphoric, and agitated. They infrequently presented with the classic manic symptoms of euphoria and grandiosity, suggesting developmental variability in the phenotypic expression of BPD. Consistent with this idea, Davis (1979) showed that children with BPD commonly presented as highly irritable, with "affectire storms" or prolonged and aggressive temper outbursts. Thus, children with BPD may not present with the classic adult manic picture. Instead, they tend to present with a more chronic, irritable, and dysphoric course (Carlson et al., 1994; McElroy et al., 1997; Weinberg and Brumback, 1976), creating a complicated, often confusing clinical picture.
In contrast to the severe mood instability that characterizes manic symptomatology, inattention, impulsivity, and hyper-activity are characteristic of both ADHD and BPD. In fact, most of the available case reports of children with BPD have commented on the symptomatic overlap between these two disorders. The overlap that causes diagnostic ambiguity between the two disorders is due to nonmood symptoms since abnormality in mood is a criterion for BPD but not for ADHD.
As early as 1952, Sadler was puzzled by children whom he initially diagnosed as hyperactive, but who went on to develop BPD. He described six such cases of "hyperactive" children with a high degree of "nervous irritability" (Sadlet, 1952). Similarly, in an adult sample, Winokur et al. (1993) found that traits of childhood hyperactivity were more common among bipolar patients and their bipolar relatives compared with depressed patients. A recent study reported that a majoricy of children with BPD have comorbid ADHD (Wozniak et al., 1995a), suggesting that the comorbidity with ADHD may be a marker of very-early-onset BPD (Faraone et al., 1997a).
Because of the high diagnostic overlap between ADHD and BPD, some investigators classify these children as having "bad" ADHD, while others view ADHD symptoms in children with BPD as prodromal to BPD (Strober et al., 1988). Despite these disagreements, it is important to stress that the controversy is nosological, since there is no question that these children exist, are severely impaired, and are difficult to treat.
How then is child psychiatry to decide whether these severely ill children have mania, ADHD, or both? As a start, it may be useful to drop diagnostic hierarchies that are not based on empirical research. From a practical perspective, that would mean making both diagnoses if warranted by the patient's history of signs and symptoms. By doing so, clinicians would be motivated to consider a wider range of therapeutic hypotheses and researchers would be able to solve the nosological puzzle posed by the comorbidity of these disorders. In the meanwhile, we should consider what the available research has to say about this issue.
Work by our group (Wozniak et al., 1995a) reported findings using systematic structured interview data which were collected from a sample of 262 consecutively referred preadolescent children (< 12 years of age). This study found that (1) 16% met full DSM-III-R diagnostic criteria for mania; (2) the clinical picture in these young manic children was characterized by severe irritability and their presentation was predominantly mixed with symptoms of major depression and mania co-occurring; (3) the course was chronic; (4) manic children often met diagnostic criteria for ADHD; and (5) manic children had severely impaired psychosocial functioning and high rates of psychiatric hospitalization (20%).
Because of concerns about the validity of the diagnosis of mania in children, our group followed this initial work with systematic evaluations of external validators which addressed issues of assessor bias, symptom overlap, and familial aggregation.
To deal with potential assessor bias, psychopathological findings in manic children,were reexamined using the empirically derived Child Behavior Checklist (CBCL). This work showed excellent convergence between CBCL scales and the structured diagnostic interview-derived diagnoses of mania and related conditions. Since the CBCL is an empirically derived instrument, these results indicate that the structured diagnostic interview findings were not due to assessor bias.
To examine whether the reported findings in manic children were the results of methodological artifacts secondary to diagnostic criterion overlap, an extensive examination of this issue was undertaken (Faraone et al., 1997b). We found that when the diagnoses of BPD and ADHD in children with both conditions were reassessed after removing the overlapping diagnostic criteria, the majority of children continued to meet criteria for both ADHD and BPD. These results indicate that the findings in children with BPD were not due to the methodological artifact of diagnostic criterion overlap between ADHD and BPD.
Third, considering that both ADHD and mania are familial disorders and that family aggregation studies are uniquely helpful in examining complex patterns of comorbidity, a family-genetic study of our manic children was undertaken (Wozniak et al., 1995b). This family-genetic study of firstdegree relatives of children with BPD and ADHD found (1) relatives of BPD+ADHD probands and ADHD probands were at significantly greater risk for ADHD than relatives of normal controls; (2) the two groups did not differ significantly from one another in their relatives' risk for ADHD; (3) an elevated risk for BPD was observed only among relatives when the proband child had BPD+ADHD but not when the proband had ADHD alone; (4) an elevated risk for major depression was found for relatives of both subgroups of ADHD probands, but the risk was greatest for relatives of probands with BPD+ADHD; (5) both ADHD and BPD occurred in the same relatives more often than expected by chance alone (i.e., they cosegregated); and (6) no significant nonrandom mating between ADHD and BPD parents was found. These findings were fully replicated in another sample of children with ADHD who had comorbid BPD (Biederman et al., 1995). Taken together, these results support the hypothesis that BPD+ADHD (or ADHD+BPD) is a familially distinct subtype of either BPD or ADHD.
Moreover, in a recent review of the extant literature, Faraone et al. (1997a) documented a bidirectional familial association between ADHD and BPD in studies of ADHD and BPD subjects. In contrast to a rate of ADHD of 15% in the children of bipolar adults, the rate in controls was only 5%, well within the known population prevalence of the disorder. Similarly, this analysis also showed that relatives of ADHD children have a twofold increase in the risk for BPD compared with relatives of controls.
We have also begun to examine the effects of mood stabilizers on the course and outcome of children with BPD (Biederman et al., in press). We did so in a sample of 59 consecutively referred pediatric patients who, at initial intake, satisfied diagnostic criteria for mania on a structured diagnostic interview. We systematically reviewed their clinical records to assess (1) the course of manic symptoms and (2) all medications prescribed at each follow-up visit. Survival analysis was used to determine the effect of mood stabilizers and other medications on the course of manic symptoms. The occurrence of manic symptoms significantly predicted the subsequent prescription of mood stabilizers, and mood stabilizers predicted decreases in manic symptoms. However, improvement was slow and associated with a substantial risk for relapse. We concluded that mood stabilizers were frequently used in manic children and their use was associated with significant improvement of manic symptoms while antidepressant, antipsychotic, and stimulant medications were not. Although preliminary, our findings suggest that mood stabilizers may be efficacious in the treatment of manic children. Using this dataset, we could also demonstrate that treatment of ADHD symptomatology with anti-ADHD agents was only efficacious after mood stabilization.
The significance of our work in juvenile BPD within and without the context of ADHD goes beyond resolving a vexing nosological question. Children with BPD may be relatively uncommon in most outpatient settings, but clinical experience suggests that they may account for a substantial number of child psychiatric hospitalizations and that they are plagued with chronic psychiatric and psychosocial disability (Kovacs and Pollock, 1995; West et al., 1995). Our identification of a nosologically distinct subgroup of children with phenotypic features compatible with the diagnosis of both ADHD and mania has provided a first step toward validating this subgroup that should lead to improved guidelines for diagnosis and, eventually, for treatment. Since prophylactic pharmacotherapy can reduce the psychiatric and psychosocial morbidity associated with BPD, clarification of nosological issues for child and adolescent BPD could benefit youngsters with ADHD who suffer from this severe disorder.
REFERENCES [to J. Biederman's affirmative]
Biederman J, Mick E, Bostic JQ et al. (in press), The naturalistic course of pharmacologic treatment of children with manic-like symptoms: a systematic chart review. J Clin Psychiatry
Biederman J, Wozniak J, Kiely K et al. (1995), CBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD. J Am Acad Child Adolesc Psychiatry 34:464-471
Carlson G, Fennig S, Bromet EJ (1994), The confusion between bipolar disorder and schizophrenia in youth: where does it stand in the 199Os? J Am Acad Child Adolesc Psychiatry 33:453-460
Davis RE (1979), Manic depressive variant syndrome of childhood: a preliminary report. Am J Psychiatry 136:702-706
Faranne SV, Biederman J, Mennin D, Wozniak J, Spencer T (1997a), Attention-deficit hyperactivity disorder with bipolar disorder: a familial subtype? J Am Acad Child Adolesc Psychiatry 36:1378-1387
Faraone SV, Biederman J, Wozniak J, Mundy E, Mennin D, O'Donnell D (1997b), Is comorbidity with ADHD a marker for juvenile-onset mania? J Am Acad Child Adolesc Psychiatry 36:1046-1055
Kovacs M, Pollock M (1995), Bipolar disorder and comorbid conduct disorder in childhood and adolescence. J Am Acad Child Adolesc Psychiatry 34:715-723
McElroy S, Strakowski S, West S, Keck P, McConville B (1997), Phenomenology of adolescent and adult mania in hospitalized patients with bipolar disorder. Am J Psychiatry 154:44-49
Sadler W (1952), Juvenile manic activity. Nerv Child 9:363-368
Strober M, Morrell W, Burroughs J, Lampert C, Danforth H, Freeman R (1988), A family study of bipolar I disorder in adolescence: early onset of symptoms linked to increased familial loading and lithium resistance. J Affet Disord 15:255-268
Weinberg WA, Brumback RA (1976), Mania in childhood. Am J Dis Child 130:380-385
West S, McElroy S, Strakowski S, Keck P, McConville B (1995), Attention deficit hyperactivity disorder in adolescent mania. Am J Psychiatry 152:271-274
Winokur G, Coryell W, Endicott J, Akiskal H (1993), Further distinctions between manic-depressive illness (bipolar disorder) and primary depressive disorder (unipolar depression). Am J Psychiatry 150:1176-1181
Wozniak J, Biederman J, Kiely K et al. (1995a), Mania-like symptoms suggestive of childhood onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 34:867-876
Wozniak J, Biederman J, Mundy E, Mennin D, Faraone SV (1995b), A pilot family study of childhood-onset mania. J Am Acad Child Adolesc Psychiatry 34:1577-1583.
NEGATIVE: RACHEL G. KLEIN, PH.D., [of New York State Psychiatric Institute] DANIEL S. PINE, M.D., [of Columbia University] AND DONALD E KLEIN, M.D. [New York State Psychiatric Institute].
Several questions about bipolar disorder (BPD) have preoccupied clinicians and researchers in child psychiatry--for example, whether attention-deficit hyperactivity disorder (ADHD) symptomatology is a frequent feature of BPD, whether ADHD symptomatology characterizes the premorbid history of adolescents and adults with BPD, and whether major depression places children at risk for BPD. Though important, these questions are not germane to the one we address, which concerns exclusively whether mania in preadolescents is erroneously diagnosed as ADHD, as postulated by Biederman and colleagues in Boston. (We use the terms mania and bipolar disorder interchangeably because this is standard practice in the child psychiatry literature.) We assume that we are not debating an occasional diagnostic failure, but a frequent error of concern to all clinicians. Were it otherwise, there would be little point to this debate.
It is informative to review the historical context of diagnostic discoveries in psychiatry. As articulated by Robins and Guze (1970), psychiatric disorders become recognized as valid by documenting multiple distinctions, i.e., phenomenology, family history, course, biology, and (we add) distinctive treatment response. A case in point is Kraepelin's subdividing psychotic patients into manic-depression and dementia praecox (schizophrenia), based on divergent course. Eventually, this subcategorization was validated further by differential treatments and brain imaging findings. In complementary fashion, the refinement of anxiety neuroses originated from observations of differential treatment responses in anxious patients with and without panic attacks. This distinction was validated further by differential course, challenge responses, and familial patterns. Such psychiatric success stories stand in sharp contrast to multiple instances in which postulated new syndromes proved misleading without the benefit of progressive validation. The supposed overlooking of mania in children with ADHD requires critical examination against this historical background.
The first point concerns the phenomenology of BPD. Clinical descriptions of mania have been remarkably consistent over the years, if not centuries, consisting of a distinct episode of elevated mood or irritability, with well-established associated features (briefly: grandiosity, flight of ideas, pressure of speech, distractibility, increased motor activity, decreased sleep, unrestrained pleasure-seeking activities), usually interspersed with episodes of major depression. No diagnostic criteria have ever been proposed for stable, continuous mania. Yet it is repeatedly stated that children labeled with BPD, unlike adults, display chronic mania. On what basis can this assertion be accepted? If DSM-IV criteria are applied, as we feel they must, this clinical feature alone precludes the diagnosis. Moreover, unlike manic adults, in whom expansive mood is usual, even if often coupled with irritability, elevated mood is rare in children labeled with BPD (Biederman et al., 1995; Milberger et al., 1995; Wozniak et al., 1995a). Consequently, we are not dealing with identical phenomenology. It appears that the question debated should be reformulated to address whether children who lack the "distinct period" requirement, and elevated mood, are misdiagnosed as having ADHD, when in fact they have BPD.
If there is frequent misattribution of manic symptoms to ADHD diagnoses in young children, childhood mania must be common, in contradiction to the general consensus that it is very rare. The most recent epidemiological study found not a single child with mania, and only about 1 per 1,000 children with hypomania among a screened sample of nearly 4,000 children (Costello et al., 1996). This low rate occurred despite the fact that the prevalence of ADHD was consistent with prior estimates. One might question whether the diagnoses, based on lay interviews, are comparable with those of Dr. Biederman's Boston group clinical samples. However, both rely on nonclinicians to elicit symptoms. One wonders whether similar diagnoses would be generated by experienced clinicians.
To avoid problems of lay interviews, the Boston group's clinicians review all diagnoses. The degree to which diagnostic decisions concord between the two methods is relevant to questions about the diagnosis of BPD. In all reports except one (Biederman et al., 1996), the agreement between lay interviewers and clinician-derived BPD diagnoses is so high that the two approaches virtually never diverge. For example, a typical report notes a 16% rate of BPD with a lc value of 0.91 (Wozniak et al., 1995a). In ordinary language, it means that in this sample, clinicians concurred in about 99% of cases identified as BPD by lay interviewers (sensitivity). Similarly, clinicians agreed with lay interviewers in about 99% of the cases not diagnosed as BPD (specificity). This remarkable overlap between individuals untrained in child psychiatry and senior child psychiatrists is inconsistent with the observation by the Boston group that "it is very difficult to make bipolar diagnoses in children" (Biederman et al., 1996, p. 1006). It seems contradictory that complicated diagnostic dilemmas are resolved simply by providing training on structured diagnostic interviews.
Several clinical findings are puzzling. Agoraphobia and social phobia are diagnosed in about a third of children labeled as having BPD (Wozniak et al., 1995a). Reticence and embarrassment in public are hardly salient in mania, nor is interference with independent travel due to anxious anticipation. Puzzlement over the clinical picture is not limited to diagnosis, but it arises also from parent ratings (Child Behavior Checklist). We do not attribute much significance to scale ratings in the diagnostic process; however, we note these because they are proposed as validating BPD (Biederman et al., 1995). Compared with children with ADHD, children labeled manic obtained elevated scores on the Withdrawn scale, i.e., likes to be alone, refuses to talk, secretive, shy, stares, sulks, underactive slow-moving, sad, withdrawn-does not get involved with others. These behaviors are clearly inconsistent with mania. Also, relatively high scores are found for complaints of aches and pains, but not for social problems. How can these findings be reconciled with the claim that mania in these children is identical with DSM-IV mania? Some confidence in the purported diagnosis may be bolstered by the reported 16% rate of psychosis (as opposed to 2% in ADHD) (Wozniak et al., 1995a) and by the relatively high rate of hospitalization during a 4-year follow-up (20%) (Biederman et al., 1996). Unfortunately, standards for psychosis are not stipulated, and hospitalization may index severity of behavioral disturbance rather than mania. Problematically, if the investigators made the decisions about hospitalization during the follow-up interval, rates of hospitalization do not contribute independently to diagnostic validity.
To its credit, the Boston group has been careful to confirm BPD in children with ADHD after removing three symptoms common to both (hyperactivity, overtalkativeness, and distractibility). By doing so, only 47% of the children labeled as having ADHD+BPD retained BPD (Milberger et al., 1995). The magnitude of the drop implies that ADHD was mistaken for mania in the majority, rather than the reverse. In another report (Wozniak et al., 1995a), only 24% were no longer labeled with BPD after excluding the three overlapping symptoms. It follows that 76% were so symptomatic that they met all seven diagnostic criteria required, in addition to affective disturbance. That such a high proportion of children exhibited all diagnostic criteria seems inconsistent with outpatient status.
In sum, the clinical descriptions of mania in the children studied by the Boston group do not fit well the classic definition of mania. The divergent criteria applied challenge the claim that we are dealing with similarly defined disorders. To accept variations in criteria for the diagnosis of mania in children requires that other features of "childhood mania" so resemble adult mania (e.g., heredity, course, treatment response) that criteria modification is in order.
The second point concerns family history. An elevated rate of BPD in relatives of children with ADHD labeled as having BPD (BPD+ADHD) is an argument advanced to support the valid presence of mania in these children. Indeed, familial concordance would provide a strong argument in support of a relationship between adult and child disorders (though one could not conclude that they were identical). However, the pattern of results does not fit well such expectations. First, rates of 3% and 7% of BPD in relatives of normal children (Biederman et al., 1996; Faraone et al., 1997a) far exceed rates reported in numerous studies, and they indicate a substantial lack of specificity for such BPD diagnoses. Second, in the initial report, the rate of BPD in adult relatives of children with BPD+ADHD is elevated compared with that in relatives of children with ADHD, but not compared with the rate in relatives of normal subjects. In contrast, the rate of BPD in preadult relatives of children with BPD+ADHD is elevated compared with normal subjects, but not compared with ADHD subjects. Only by combining relatives of all ages is an excess of BPD relatives found in children labeled manic compared with both the ADHD and normal groups (Biederman et al., 1996).
In the second study, no significant excess of BPD without ADHD occurred in relatives of children with ADHD and BPD. Most critically, the results do not concord with studies of offspring of adults with BPD, in whom no excess of BPD or ADHD has been reported (Carlson and Weintraub, 1993; Goodwin and Jamison, 1990). How can these contradictory findings be reconciled? Since the weak familial relationship for BPD in the Boston studies may reflect shared diagnostic biases, as the investigators themselves acknowledge, e.g., "it is conceivable that the increased rate of BPD+ADHD observed among relatives of BPD+ADHD is due to a consistent diagnostic error that affects both probands and relatives" (Wozniak et al., 1995b, p. 1581), familial validation has not been established. At the same time, we concur with the authors that the scarcity of children with BPD, in some reports, limits opportunities for determining group differences.
The third issue concerns longitudinal course. In a 4-year prospective follow-up of children with ADHD and normal children, Biederman et al. (1996) reported that 2% of normal control children developed BPD. Remarkably, this rate exceeds the disorder's lifetime prevalence in adults, and it speaks further to diagnostic nonspecificity for BPD as defined. In addition, 12% of children with ADHD developed BPD during the 4-year follow-up. So far, no longitudinal study of ADHD children spanning from one to two decades has identified a single instance of BPD. It is conceivable that mania might be missed often in children, but very unlikely in adults.
Finally, the high frequency of BPD (17% and 16%) (Faraone et al., 1997b; Wozniak et al., 1995a) among referrals to a clinic, described as typical of child psychiatry outpatient clinics, suggests that childhood BPD disappears over time since drastically lower rates occur among adult outpatients. This conclusion would be erroneous if adults with mania were unlikely to come to clinical attention, or if virtually all were institutionalized, but neither is the case. In sum, longitudinal studies, and other pertinent findings, do not support the essential congruence between childhood mania as defined by the Boston group and adult mania.
As we note, treatment response can also contribute to diagnostic validation. Treatment inquiry has been eschewed because of the claim that precise clinical diagnosis takes priority (Wozniak and Biederman, 1996). Treatment effects inform and facilitate diagnostic refinements; they do not detract. The absence of concurrent therapeutic observations is regrettable.
A report that some depressed children previously treated with tricyclics switched to mania (Geller et al., 1993) is relevant to whether mania is misdiagnosed as ADHD. If a substantial proportion of children with ADHD were latent bipolars, manic switching should occur in ADHD children treated with tricyclics or stimulants. If manic exacerbation ever happens, it must be truly exceptional--we have been unable to identify even a single such report. There is a long tradition of treating children with lithium. Limited data suggest lithium efficacy in childhood BPD defined by discrete episodes (DeLong and Aldershof, 1986). Other reports are inconsistent and not encouraging.
To conclude, the consistent atypically high rate of mania reported by the Boston group calls into question the congruence of their diagnosis with the disorder described in the DSM-IV. In a comprehensive, lucid commentary, Carlson (1995) pointedly noted that in her own studies, endorsement of symptoms of mania represented a nonspecific index of severity rather than a specific indication of BPD. Perhaps that is a large part of the diagnostic confusion. Children with ADHD comorbid with conduct disorder and/or violent explosive outbursts may mimic aspects of manic presentation, but they do not display a relapsing/remitting symptomatic picture, except perhaps in response to altered living circumstances (e.g., not in school, parents not around). Such children pose diagnostic problems, but the children do not meet criteria for mania. The truism that further research may alter our views applies here as in all instances, but little will be gained from further investigations that do not adopt established criteria. Conforming to the DSM-IV should be feasible because deviations from standard diagnostic criteria are not the rule in major contributors' writings (Carlson, 1995; Geller and Luby, 1997; Weller et al., 1995). Moreover, clinical discoveries require direct, preferably longitudinal clinical observations, and we concur with Weller et al. (1995) that there is no substitute for expert, direct clinical assessments.
In sum, the proposed evidence for validity of childhood mania in ADHD is lacking. Clinical, genetic, longitudinal, and therapeutic data all fail to document that BPD masquerades as ADHD.
REFERENCES [to Negative position]
Biederman J, Faraone S, Mick E et al. (1996), Attention-deficit hyperactivity disorder and juvenile mania: an overlooked comorbidity? J Am Acad Child Adolesc Psychiatry 35:997-1008
Biederman J, Wozniak J, Kiely K et al. (1995), CBCL clinical scales discriminate prepubertal children with structure interview--derived diagnosis of mania from those with ADHD. J Am Acad Child Adolesc Psychiatry 34:464-471
Carlson GA (1995), Identifying preptabertal mania. J Am Acad Child Adolesc Psychiatry 34:750-753
Carlson GA, Weintraub S (1993); Childhood behavior problems and bipolar disorder: relationship or coincidence? J Affect Disord 28:143-153
Costello EJ, Angold A, Burns BJ et al. (1996), The Great Smoky Mountains study of youth: goals, design, methods, and the prevalence of DSM-III-R disorders. Arch Gen Psychiatry 53:1129-1136
DeLong GR, Aldershof AL (1986), Long-term experience with lithium treatment in childhood: correlation with clinical diagnosis. J Am Acad Child Psychiatry 26:389-394
Faraone SV,, Biederman J, Mennin D, Wozniak J, Spencer T (1997a). Attention deficit hyperactivity disorder with bipolar disorder: a familial subtype? J Am Acad Child Adolesc Psychiatry 36:1378-1387
Faraone SV, Biederman J, Wozniak J, Mundy E, Mennin D, O'Donnell D (1997b), Is comorbidity with ADHD a marker for juvenile-onset mania? J Am Acad Child Adolesc Psychiatry 36:1046-1055
Geller B, Fox LW, Fletcher M (1993), Effect of tricyclic antidepressants on switching to mania and on the onset of bipolarity in depressed 6- to 12 year-olds. J Am Acad Child Adolesc Psychiatry 32:43-50
Geller B, Luby J (1997), Child and adolescent bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 36:1168-1176
Goodwin FK, Jamison KR (1990), Manic-Depressive lllness. New York: Oxford University Press
Milberger S, Biederman J, Faranne SV, Murphy J, Tsuang MT (1995), Attention deficit hyperactivity disorder and comorbid disorders: issues of overlapping symptoms. Am J Psychiatry 152:1793-1799
Robins EN, Guze S (1970), Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 126:983-987
Weller EB, Weller RA, Fristad MA (1995), Bipolar disorder in children: misdiagnosis, underdiagnosis, and future directions. J Am Acad Child Adolesc Psychiatry 34:709-714
Wozniak J, Biederman J (1996), Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry 35:1569-1570
Wozniak J, Biederman J, Kiely K et al. (1995a), Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 34:867-876
Wozniak J, Biederman J, Mundy E, Mennin D, Faraone SV (1995b), A pilot family study of childhood-onset mania. J Am Acad Child Adolesc Psychiatry 34:1577-1583
AFFIRMATIVE REBUTTAL: BIEDERMAN
I thank Dr. Klein and colleagues for clarifying their views on attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) in a forum that will allow our colleagues to evaluate the relevant data. Because I wholeheartedly endorse their appeal to the methods of Robins and Guze (1970) as the touchstone for validating psychiatric diagnoses, the reader can rest assured that the resolution to this debate should rely on the facts and not be swayed by preconceived ideas about the disorders in question. Thus, like Klein et al., I will address phenomenology, family history, course, and treatment response as they relate to the question, Is mania mistaken for ADHD in prepubertal children?
In their discussion of phenomenology, Klein et al. suggest that the chronic mania of bipolar children precludes a DSM-IV diagnosis of BPD because they lack a distinct period of elevated mood or irritability. This is not true. Bipolar children are chronic in the sense that they never fully remit symptoms or attain their expected level of psychosocial functioning. They do, however, have "distinct periods" during which they are fully symptomatic. This concurs with the DSM-IV statement that "Although the majority of individuals with Bipolar I disorder return to a fully functional level between episodes, some (20%-30%) continue to display mood lability and interpersonal or occupational difficulties" (American Psychiatric Association, 1994, p. 353). Thus, although we agree with Klein et al. that this chronic picture with primarily irritable mood is not classic mania, we disagree with their statement that the BPD diagnosis is inappropriate.
Notably, the atypical picture of childhood mania is a reproducible feature of the disorder. In a recent review of the past 10 years of research into child and adolescent BPD, Geller and Luby (1997) concluded, "Available data strongly suggest that prepubertal-onset BPD is a nonepisodic, chronic, rapidcycling, mixed manic state that may be comorbid with... ADHD . . . and CD [conduct disorder] or have features of ADHD and/or CD as initial manifestations" (p. 1168). Thus, it may well be that the atypical picture of childhood mania points to ways in which the DSM-IV should be revised to account for developmental variability in symptom expression. Such variability is well recognized for depression and has been described for mania (Carlson, 1984), even though it has not been accepted for DSM-IV.
Klein et al. correctly note that the Great Smoky Mountains epidemiological study of children found no cases of mania (Costello et al., 1996). But they fail to mention two key methodological aspects of that study. First, the authors reported the 3-month prevalence of mania, not the lifetime history. Thus, to receive a diagnosis of mania, children had to meet diagnostic criteria during the 3-month period queried by the assessment. This approach provides valuable data but underestimates the lifetime prevalence. That study also found very few cases of depression (the 3-month prevalence was 0% for males and 0.07% for females). Should we conclude that childhood depression is exceedingly rare? Moreover, the Great Smoky Mountains study ascertained children from the public school's database. Since many bipolar children cannot be maintained in public school settings, it is not surprising that no cases were identified. Moreover, the failure of an epidemiological study to diagnose BPD does not detract from the idea that many BPD cases are mistaken for ADHD. In fact, if BPD is frequently mistaken for ADHD, then one would expect to see very low rates of BPD in most studies.
Another phenomenological concern voiced by Klein et at. is the fact that, in our research, psychiatrists usually agree with the ratings of bipolar symptoms made by lay interviewers. What this finding means is that when psychiatrists listen to audiotaped interviews, they usually agree with the ratings of symptoms made by the interviewer. Although our high level of reliability does not guarantee validity, it is a prerequisite. So it seems odd to be criticized on this point. It seems that Klein et al. confuse diagnostic complexity with diagnostic reliability. The diagnostic complexities of pediatric BPD are due to its high level of comorbidity with other disorders. This can lead the unsophisticated clinician to deny diagnostic possibilities based on prejudices and misconceptions. It is not, however, difficult to capture the symptoms of mania if one focuses on the symptoms that define the disorder in a manner that is not obscured by preconceptions about whether the symptoms have been caused by a comorbid condition.
Klein et al. suggest that my group's finding of comorbid anxiety disorders among bipolar children challenges the validity of their BPD diagnoses. What they neglect to note is that others have reported similar findings in adolescents and adults. Carlson and Kashani (1988) found that nonreferred adolescents with manic symptoms had increased rates of anxiety disorders. Bashir et al. (1987) noted that anxiety disorders were present in 53% of 30 adolescents with diagnosed 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 Dilsaver, 1995). Lewinsohn and colleagues' (1995) study of a representative community sample of 1,700 adolescents also found high rates of comorbidity between bipolar and anxiety disorders. Thus, although Klein et al. believe that anxious symptoms are inconsistent with mania, they are a reproducible feature of BPD, not an artifact of the diagnostic procedures used by my research team.
Another fact ignored by Klein et al. is that children with ADHD frequently suffer from major depression. This has been consistently observed in clinical and epidemiological studies (Angold and Costello, 1993; Biederman et al., 1991). Given that depression often is a precursor to BPD, one would expect some children with ADHD to be at risk for the latter disorder.
I am puzzled by the claim that the high rates of psychosis in our manic children are viewed as meaningless. I would like to remind my colleagues that the definition of psychotic phenomena includes delusions and hallucinations, hardly irrelevant clinical phenomena. Similarly puzzling is the suggestion that the very high rate of psychiatric hospitalization observed in our manic children is an artifact of the investigators' involvement in hospitalization decisions. I hope that Klein et al. do not suspect that we have used psychiatric hospitalization of young children to corroborate our diagnostic formulations. In fact, most of the psychiatric hospitalizations in our sample of manic children occurred before they were seen in our program. Thus, decisions about hospitalization were outside the control of the investigators. It is precisely our point that the clinical features of children with ADHD and mania that lead to their psychiatric hospitalization indicate the presence of mania, not ADHD. These children are not admitted because of failure to complete homework.
In summary, I agree with Klein et al. that the phenomenology of pediatric BPD is not "classic" but assert that it does fit DSM-IV criteria, although its predominant irritability and chronicity may make it difficult, in some cases, to distinguish from ADHD.
Following the outline of Robins and Guze (1970), Klein et al. next address the issue of family history. But their review ignores key data and leads them to an incorrect conclusion. They incorrectly state that our family studies found a 7% rate of BPD in relatives of normal children. The rates of BPD in relatives were 0% in our family study of boys with DSM-III-defined attention deficit disorder (Biederman et al., 1990), 0% in our family study of girls with attention deficit disorder (Faraone et al., 1991), and 2% in our study of boys with ADHD (Biederman et al., 1992).
Another error of Klein et al. is seen in their statement that studies of adults with BPD find no ADHD in their offspring. Elsewhere, we reviewed the literature for family studies that assessed both ADHD and BPD (Faraone et al., 1997). Studies that examined rates of ADHD (or ADD, hyperactivity, etc.) among the children of bipolar patients all found higher rates of ADHD among these children compared with controls (Grigoroiu-Serbanescu et al., 1989; Hammen et al., 1990; Kron et al., 1982; Zahn-Waxler et al., 1988). Although studies of relatives of children with ADHD have been less consistent than studies of bipolar families, our meta-analysis found an elevation of BPD in ADHD families compared with control families (Bhatia et al., 1991; Biederman et al., 1990, 1992; Cantwell, 1972; Faraone et al., 1991; Stewart and Morrison, 1973). Notably, none of the studies of bipolar families were performed by my research group. Thus, on the basis of the available data, I conclude that family studies do find a link between ADHD and BPD.
I agree with Klein et al. that no follow-up study of ADHD into adulthood has shown children with ADHD to be at risk for BPD in adulthood. Few such studies exist, and few examine bipolar outcomes. Moreover, many of these studies systematically exduded subjects who might have had a BPD diagnosis. For example, in their follow-up study, Mannuzza et al. (1993) excluded hyperactive children whose primary reason for referral was aggressive behavior. Given that bipolar children are extremely aggressive, it seems unlikely that they would have been ascertained into that study. Thus, the best summary of follow-up studies of ADHD is that they are incondusive.
I agree with Klein et al. that the absence of treatment data is regrettable. Clinical experience suggests that manic ADHD children respond well to mood-stabilizing agents (Wozniak and Biederman, 1996), which is consistent with the assertion that their mania is not simply "bad" ADHD. Moreover, in a recent report, Strober et al. (in press) showed that adolescent manics with a history of ADHD had a less robust response to lithium treatment than manics without ADHD. He speculated that some cases of childhood onset of ADHD might be a developmentally early expression of BPD and that their muted response to treatment might reflect the undertreatment of very early-onset BPD. This idea is clearly consistent with the hypothesis that untreated mania leads to "kindling," a chronic course, and treatment resistance (Post et al., 1986). Clearly, mistaking BPD for ADHD can have grave clinical implications.
At the 1996 Annual Meeting of the AACAP, I presented data documenting selective responsivity of manic children to mood stabilizers (Biederman, 1996). The publication of those data has been delayed because of reviewers who question the validity of prepubertal BPD. This is the quiet tragedy of childhood mania: Many psychiatrists face children with ADHD who have horrifying life-long histories of irritable and aggressive mood but have no access to relevant research because reviewers dispute the existence of childhood mania.
In conclusion, I assert that childhood mania exists and that it is often misdiagnosed as "bad" ADHD. This idea challenges preconceptions and, like other new ideas in the history of science and medicine, has been dismissed by some and castigated by others. Of course, the earth was thought to be fiat and the sun was thought to circle the earth. Jenner's smallpox vaccine was ridiculed when initially proposed and Marshall and Warrens discovery that Helicobacterpylori is etiologically linked to peptic ulcers was ridiculed and shelved for decades. Given the severity of childhood mania and its impact on children and their families, I am hopeful that its routine recognition and treatment will not be similarly delayed.
REFERENCES [to Biederman's Affirmative Rebuttal]
American Psychiatric Association (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association
Angold A, Costclio EJ (1993), Depressive comorbidity in children and adolescents: empirical, theoretical and methodological issues. Am J Psychiatry 150:1779-1791
Bashir M, Russell J, Johnson G (1987), Bipolar affectire disorder in adolescence: a 10-year study. Aust NZ J Psychiatry 21:36-43
Bhatia M, Nigam V, Bohra N, Malik S (1991), Attention deficit disorder with hyperactivity among pediatric outpatients, J Child Psychol Psychiatry 32:297-306
Biederman J (1996), In: Scienufic Proceedings of the Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Philadelphia
Biederman J, Faraone SV, Keenan K et al. (1992), Further evidence for family genetic risk factors in attention deficit hyperactivity disorder (ADHD): patterns of comorbidity in probands and relatives in psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 49:728-738
Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT (1990), Family genetic and psychosocial risk factors in DSM-III attention deficit disorder. J Am Acad Child Adolesc Psychiatry 29:526-533
Biederman J, Newcorn J, Sptich S (1991), Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148:564-577
Cantwell DP (1972), Psychiatric illness in the families of hyperactive children. Arch Gen Psychiatry 27:414-417
Carlson GA (1984), Classification issues of bipolar disorders in childhood. Psychiatr Der 2:273-285
Carlson GA, Kashani JH (1988), Manic symptoms in a non-referred adolescent population. J Affect Disord 15:219-226
Chen Y, Dilsaver S (1995), Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area survey. Am J Psychiatry 152:280-283
Costclio EJ, Angold A, Burns BJ et al. (1996), The Great Smoky Mountains study of youth: goals, design, methods, and the prevalence of DSM-III-R disorders. Arch Gen Psychiatry 53:1129-1136
Faraone SV, Biederman J, Keenan K, Tsuang MT (1991), A family-genetic study of girls with DSM-III attention deficit disorder. Am J Psychiatry 148:112-117
Faraone SV, Biederman J, Mennin D, Wozniak J, Spencer T (1997), Attention deficit hyperactivity disorder with bipolar disorder: a familial subtype? J Am Acad Child Adolesc Psychiatry 36:1378-1387
Geller B, Luby J (1997), Child and adolescent bipolar disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 36:1168-1176
Grigoroiu-Serbanescu M, Christodorescu D, Jipescu I, Totoescu A, Marinescu E, Ardeleau V (1989), Psychopathology in children aged 10-17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology. J Affect Disord 16:167-179
Hammen C, Burge D, Burney E, Adrian C (1990), Longitudinal study of diagnoses in children of women with unipolar and bipolar affectire disorder. Arch Gen Psychiatry 47:1112-1117
Kron L, Decina P, Kestenbaum CJ, Farber S, Gargan M, Fieve R (1982), The offspring of bipolar manic-depressives: clinical features. In: Developmental and Clinical Studies, Feinstein SC, ed. Chicago: University of Chicago, pp 273-291
Lewinsohn P, Klein D, Seeley J (1995), Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 34:454-463
Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M (1993), Adult outcome of hyperactive boys: educational achievement, occupational rank and psychiatric status. Arch Gen Psychiatry 50:565-576
Post R, Rubinow D, Ballenger D (1986), Conditioning and sensitization in the longitudinal course of affectlye illness. Br J Psychiatry 149:191-201
Robins E, Guze SB (1970), Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 126: 983-987
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Stewart MA, Morrison JR (1973), Affectire disorders among the relatives of hyperactive children. J Child Psychol Psychiatry 14:209-212
Strober M, DeAntonio M, Schmidt-Lacker S, Freeman R, Lampert C, Diamond J (in press), Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania. J Affect Disord
Wozniak J, Biederman J (1996), A pharmacological approach to the quagmire of comorbidity in juvenile mania. J Am Acad Child Adoles Psychiatry 35:826-828
Zahn-Waxler C, Mayfield A, Radke-Yarrow M, McKnew D, Cytryn L, Davenport Y (1988), A follow-up investigation of offspring of parents with bipolar disorder. Am J Psychiatry 145:506-509
NEGATIVE REBUTTAL: KLEIN, PINE, AND KLEIN
The question is whether bipolar disorder (BPD), or mania, is frequently mistakenly diagnosed as attention-deficit hyperactivity disorder (ADHD) among prepubertal children. To begin with, we know of no evidence that documents that BPD accounts for most hospitalizations of children, as stated by Dr. Biederman.
Supportive affirmative evidence is garnered from retrospective reports of childhood histories of hyperactive behavior in adults and adolescents with BPD, and a clinical report of hyperactive children who developed BPD. These observations raise the possibility that childhood ADHD is a precursor of adult BPD, but they are irrelevant to the claim that BPD is misdiagnosed as ADHD in children.
Dr. Biederman's affirmative statement makes several points we addressed in our statement. First, a major distinction of BPD is its episodic, on-and-off nature, with associated features that parallel directly affective alterations. Dr. Biederman claims that in children BPD is chronic, as noted also by others. However, the two systematic clinical studies quoted to document this point report on adolescents. Our debate is not about BPD in adolescents, but in prepubertal children.
At the same time, the very studies quoted do not support the claim of major clinical differences between adolescent and adult BPD. Only one study has reported systematic direct comparisons of adolescents and adults (McElroy et al., 1997). It is described by Dr. Biederman as supporting the distinct nature of BPD in children, but we disagree. As stated, the study does not include children. In addition, adolescents and adults did not differ with regard to features claimed to be characteristic of childhood BPD by Dr. Biederman. The younger group was not more chronic; it did not have less mania, not more irritability, not less accelerated speech, and not more depressive symptoms. Some differences were found between the adolescents and adults--among others, a relatively higher rate of mixed BPD and fewer psychotic symptoms occurred in the younger patients. However, the group overlap is large (as an example, psychotic symptoms occurred in 75% of the adolescents and 91% of the adults). The findings do not suggest, nor do the investigators, that diagnostic criteria of BPD require modification in preadulthood.
Second, we disagree with the claim that Child Behavior Checklist (CBCL) results are validating of BPD in the children studied by Dr. Biederman and his group. The CBCL is not a diagnostically derived instrument and it has never been validated in BPD. Score differences more likely reflect differences in severity than typology.
Third, family data are not unambiguously supportive of the relationship of BPD to ADHD in children. Ambiguity stems from the mixed results, and the potential for common biases in the application of BPD criteria in children and parents.
Fourth, treatment observations reported in Biederman's statement are intriguing, but they are insufficiently documented to be considered supportive evidence. At the same time, the reported inefficacy of antipsychotics is puzzling, since they are standard treatments in BPD and also effective in ADHD. We look forward to randomized, double-blind, placebo-controlled studies that document the efficacy of mood stabilizers and the failure of psychostimulants in children labeled as having BPD by Dr. Biederman and his team, and opposite effects in those with ADHD.
We heartily agree that diagnostic hierarchies should be avoided, but the relevance of the comment is obscure because the DSM-IV does not include hierarchies for ADHD and BPD, nor were there any in DSM-III or III-R.
Most important, we take strong exception to the statement that the children labeled as having BPD "met full DSM-III-R diagnostic criteria for mania," as stated in Dr. Biederman's statement. The children failed criterion A, which requires a distinct period of affective disruption. The most modest goal of medical classification is a common vocabulary. The DSM-III introduced clinical inclusion and exclusion criteria that would, for the first time in history, make this minimal standard possible. Unless we adhere to it, there is little hope of meaningful communication and scientific progress.
McElroy SL, Strakowski SM, West SA, Keck PE, McConville BJ (1997), Phenomenology of adolescent and adult mania in hospitalized patients with bipolar disorder. Am J Psychiatry 154:44-49
The debaters in this section were asked to respond to the resolution from their respective viewpoints, the opinions they express may not necessarily reflect their true positions nor do they reflect the opinion of the Journal. Readers are encouraged to submit their comments about these issues as Letters to the Editor.
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 37:10, OCTOBER 1998
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