Comorbidity ofAttention Deficit Hyperactivity Disorder ... · COMORBIDITY WITH CONDUCT DISORDER Attention deficit hyperactivity disorder andconduct disorder have been found tooccur

564 Am J Psychiatry 148:5, May 1991

Comorbidity of Attention Deficit Hyperactivity Disorder

With Conduct, Depressive, Anxiety, and Other Disorders

Joseph Biederman, M.D., Jeffrey Newcorn, M.D., and Susan Sprich, B.A.

Qbjective: Attention deficit hypethctivity disorder is a heterogeneous disorder of unknownetiology. Little is known about the comorbidity of this disorder with disorders other thanconduct. Therefore, the authors made a systematic search of the psychiatric and psycholog-ical literature for empirical studies dealing with the comorbidity of attention deficit hyper-activity disorder with other disorders. Data Collection: The search terms included hyperac-tivity, hyperkinesis, attention deficit disorder, and attention deficit hyperactivity disorder,cross-referenced with antisocial disorder (aggression, conduct disorder, antisocial disorder),depression (depression, mania, depressive disorder, bipolar), anxiety (anxiety disorder, anx-iety), learning problems (learning, learning disability, academic achievement), substanceabuse (alcoholism, drug abuse), mental retardation, and Tourette’s disorder. Findings: Theliterature supports considerable comorbidity of attention deficit hyperactivity disorder withconduct disorder, oppositional defiant disorder, mood disorders, anxiety disorders, learningdisabilities, and other disorders, such as mental retardation, Tourette’s syndrome, and bor-derline personality disorder. Conclusions: Subgroups of children with attention deficit hy-peractivity disorder might be delineated on the basis ofthe disorder’s comorbidity with otherdisorders. These subgroups may have differing risk factors, clinical courses, and pharmaco-logical responses. Thus, their proper identification may lead to refinements in preventive andtreatment strategies. Investigation of these issues should help to clarify the etiology, course,and outcome of attention deficit hyperactivity disorder.

(AmJ Psychiatry 1991; 148:564-577)

A ttention deficit hyperactivity disorder is a hetero-geneous disorder of unknown etiology. The prey-

alence of the disorder has been estimated to range from2% (1) in primary care pediatric samples to 6% (2)and 9% (3) in large-scale population studies of school-age children. Attention deficit hyperactivity disorder isone of the most common sources of referrals to familyphysicians, pediatricians, pediatric neurologists, andchild psychiatrists. Its impact on society is enormous interms of financial cost, stress to families, disruption inschools, and the potential for leading to criminalityand substance abuse (4).

In recent years, evidence has been accumulating re-garding high levels of comorbidity of attention deficithyperactivity disorder with a number of disorders, in-cluding mood and anxiety disorders as well as conduct

Received April 20, 1990; revision receivedjuly 30, 1990; acceptedAug. 29, 1990. From the Pediatric Psychopharmacology Unit, Child

Psychiatry Service, Massachusetts General Hospital and HarvardMedical School, Boston, and the Department of Psychiatry, MountSinai School of Medicine, New York. Address reprint requests to Dr.Biederman, Pediatric Psychopharmacology Unit (ACC 725), Massa-chusetts General Hospital, Fruit St., Boston MA 02114.

Copyright C 1991 American Psychiatric Association.

disorder. This high level of comorbidity has been

found in culturally and regionally diverse epidemio-logic samples (i.e., New Zealand and Puerto Rico) (2,

3, 5) as well as in clinical samples (6), indicating thatattention deficit hyperactivity disorder is most likely a

group of conditions with potentially different etiologicand modifying risk factors and different outcomesrather than a single homogeneous clinical entity.

Comorbidity raises fundamental questions as towhether psychiatric disorders are discrete and inde-

pendent disease entities (7). Comorbidity pervasivelyaffects research and clinical practice as a result of itsinfluence on diagnosis, prognosis, treatment, andhealth care delivery (8). From the research perspective,subgroups of patients with attention deficit hyperac-tivity disorder and comorbid disorders may representmore homogeneous subgroups of patients with atten-tion deficit hyperactivity disorder. From the clinicalperspective, subgroups of patients with attention def-icit hyperactivity disorder and comorbid disorders mayrespond differentially to specific therapeutic ap-proaches. From the public health perspective, suchsubgroups may be at high risk for the development ofsevere psychopathology. Subgrouping children with

BIEDERMAN, NEWCORN, AND SPRICH

Am J Psychiatry I 48:5, May 1991 565

attention deficit hyperactivity disorder may permit thedevelopment of early intervention strategies. This lat-ter aspect is particularly important in the light of long-term follow-up studies of children with attention def-icit hyperactivity disorder (9, 10), which indicate thata subgroup of subjects with attention deficit hyperac-tivity disorder and comorbid disorders have a pooreroutcome as evidenced by significantly greater social,emotional, and psychological difficulties. Although thecomorbidity of psychiatric disorders has been studiedin adult psychiatry as a topic of major practical andtheoretical significance (1 1), research data on attentiondeficit hyperactivity disorder have only recently beenanalyzed with comorbidity taken into account. There-fore, it remains to be determined whether researchfindings previously reported in children with attentiondeficit hyperactivity disorder are related to the atten-tion deficit hyperactivity disorder itself, the existenceof comorbid disorders, or the combination of both(12).

Several competing hypotheses have been proposedto account for patterns of comorbidity (12): 1) thecomorbid disorders do not represent distinct entitiesbut, rather, are the expression of phenotypic variabil-ity of the same disorder, 2) each of the comorbid dis-orders represents distinct and separate clinical entities,3) the comorbid disorders share common vulnerabili-ties (13), either genetic (genotype), psychosocial (ad-versity), or both, 4) the comorbid disorders represent adistinct subtype (genetic variant) within a heteroge-neous disorder (13) (i.e., attention deficit hyperactivitydisorder plus conduct disorder may be a subtype ofattention deficit hyperactivity disorder), 5) one syn-drome is an early manifestation of the comorbid dis-order (i.e., attention deficit hyperactivity disorder is anearly manifestation of a conduct or mood disorder),and 6) the development of one syndrome increases therisk for the comorbid disorder (i.e., attention deficithyperactivity disorder increases the risk for conduct ormood disorder). Investigation of these issues shouldhelp to clarify the etiology, course, and outcome ofattention deficit hyperactivity disorder.

The development of a conceptual model for under-standing the high rate of comorbidity of other disor-ders in attention deficit hyperactivity disorder is corn-plicated by controversy regarding the validity ofattention deficit hyperactivity disorder itself as a dis-tinct clinical entity. Disagreements remain as to whichof the multiple symptom domains represented in thecriteria for attention deficit hyperactivity disordershould be viewed as constituting the core deficit (i.e.,inattentiveness versus hyperactivity), the categorical ortypological nature of the medically dominated diag-nostic system versus a dimensional approach to classi-fication, and whether pervasive or situational symp-toms should be required for diagnosis. For example, anumber of authorities have argued that evidence forthe validity of attention deficit hyperactivity disorder islimited to a rather severe or pervasive type of the dis-order (14-17). Despite this controversy, however, an

extensive body of literature derived from longitudinalfollow-up studies (10, 18, 19), treatment studies (20),psychosocial and developmental correlates (21), andfamily-genetic studies of male (6, 22) and female (23)probands support the concurrent and predictive valid-ity of the broad conceptualization of attention deficithyperactivity disorder as proposed in DSM-III andDSM-III-R.

Despite the thousands of scientific articles and themany review articles, books, and book chapters onattention deficit hyperactivity disorder in the medical,psychological, and educational literature, little is knownabout the comorbidity of this disorder with other dis-orders. This review examines the available literatureon the extent and importance of comorbidity withother disorders in the syndrome of attention deficithyperactivity disorder. We conducted a systematicsearch of the psychiatric and psychological literaturefor empirical studies dealing with the comorbidity ofattention deficit hyperactivity disorder with other dis-orders. The search terms included hyperactivity, hy-perkinesis, attention deficit disorder, and attentiondeficit hyperactivity disorder, cross-referenced withantisocial disorder (aggression, conduct disorder, an-tisocial disorder), depression (depression, mania, de-pressive disorder, bipolar), anxiety (anxiety disorder,anxiety), learning problems (learning, learning disabil-ity, academic achievement), substance abuse (alcohol-ism, drug abuse), mental retardation, and Tourette’sdisorder. Since citation of every published article onthis topic is beyond the scope of this review, we se-lected for citation representative studies that were con-ducted with the most sophisticated methods. Althoughthe DSM-III-R definitions of attention deficit hyperac-tivity disorder and related disorders anchor this re-view, many of the studies described here used othermeans of classification, including DSM-II, DSM-III at-tention deficit disorder, and dimensional descriptionsof clinical syndromes. For simplicity of exposition, thenames of DSM-III-R categories will be used generi-cally unless otherwise specified.

COMORBIDITY WITH CONDUCT DISORDER

Attention deficit hyperactivity disorder and conductdisorder have been found to occur together in 30% to50% of cases in both epidemiologic (2, 3) and clinical(6, 24-34) samples (table 1). Whether attention deficithyperactivity disorder and conduct disorder constituteseparate symptom domains or diagnostic categorieshas been the topic of considerable debate (7, 35, 36,40, 47-49; unpublished 1989 paper by B.B. Lahey andC.L. Carison).

Two central positions concerning the relationshipbetween attention deficit hyperactivity disorder andconduct disorder can be identified: attention deficit hy-peractivity disorder and conduct disorder are indistin-guishable (complete overlap), or they are either par-tially or completely independent. The position that

Age

(years)

l2�’

8-1 1d

9b

Children

Sex

M

M, F

MM, F

MM

Type of Study

and/or Comparison

CD vs. ADD+CD

C

226 Community sample109 Schoolchildren rated hy-

peractive by teachers175 ClInically referred

52 Clinically referred

Year

1979

1980

19801981

19811983

1983

1984

1985

1985

1985

1986

1986

S_l3c� M 67 Clinically referred to childpsychiatry; given diag-nosis of hyperactivity

s-i 1d M, F 146 Clinically referred andcontrol

16�23�I M 201 Referred for hyperactivity;normal control

9 b M, F 926 Community sample

Author

Offord et at. (35)

Lahey et at. (36)

Sandberg et al. (37)Prinz et al. (29)

Stewart et al. (25)August et al. (38)

August and Stewart�39)

Thorley (40)

Gittelman et al. (18)

McGee et al. (5)

Weiss et al. (10)

Shapiro and Garfinkel(27)

Taylor et al. (15)

Taylor et al. (16)

Anderson Ct al. (2)

Biederman et al. (24)

Loney (31)

Milich et al. (34)

Reeves et al. (41)

Bird et al. (3)

Kiorman et al. (42)

Lahey et al. (43)

Loeber et al. (19)

Barkley et al. (44)

Farrington et al. (45)

2l_33c�

7�l2”

6-10d

M, F

M, F

M

1986 6-10d M

M, F

M

M

M, F

M, F

M, F

M, F

M

M, F

M

M, F

M

1987

1987

1987

1987

1987

1988

1988

1988

1988

1989

1989

1989

1989

1989

1991

I 1b

6-17”

6-12”

5-12”

4-16”

6-12”

6-13”

C

6-13”

8-25”

6-13”

16-23”

4-16”

6-17’�

76 Clinically referred

105 Referred

386 Probability sample frompopulation of Puerto Rico

63 Referred to pediatrics, neu-rology, or psychiatry

86 Outpatients referred for psy-chological assessment

187 Volunteers in 4th, 7th, and10th grades

74 Clinically referred

41 1 Nonreferred schoolchildren

103 C

372 Clinically referred; control

Szatmari et al. (21)

Faraone et al. (46)

Review; ADDH vs. ADD

Follow-up study

M, F 2,697 Nonreferred

M 125 Clinically referred; normalcontrol

COMORBIDITY OF ATfENTION DISORDER

566 Am J Psychiatry 148:5, May 1991

TABLE 1. Representative Studies of Comorbid Attention Deficit Hyperactivity Disorder and Conduct Disorder

Subjects

Lahey and Carlson(unpublished)

Mannuzza et at. (4)

N Type

66 Court cases

109 Nonreferred schoolchildren

104 Referred; control

315 Nonreferred schoolchildren

60 Clinically referred for anti-social or disruptive be-havior

64 Clinically referred for anti-social or disruptive be-havior

792 Nonreferred; subset of 53given diagnosis of ADD

42e Clinically referred; normalcontrol

_c Review of previous work

ADDH vs. CDHyperactivity vs. hyperactivity+

aggressive sjrmptomsADDH vs. CD vs. ADDH+CDFollow-up study; hyperactivity vs.

hyperactivity+CD

ADD with vs. without family his-tory of antisocial disorder

Prospective longitudinal study; hy-peractivity vs. CD

Prospective longitudinal follow-upstudy; hyperactive vs. control

Epidemiologic study

Prospective 15-year follow-upstudy; hyperactive vs. control

Epidemiologic study

Cluster analysis

C

Epidemiologic study

Family study; ADD vs. ADD+OPDvs. control

C

Follow-up; ADD vs. CD vs. ADD+CD vs. other diagnoses

ADDH vs. ADDH+CD vs. anxietyvs. control

Two-stage epidemiologic study

Methylp�hemdate vs. placebo;ADHD vs. ADHD+a�gressivesymptoms vs. borderline ADHD

Family study; ADHD vs. ADHD+CD vs. CD vs. control

Follow-up study; ADD+CD vs.ADD vs. CD vs. remainder

Drug study; ADHD with vs. with-out aggressive symptoms

Prospective longitudinal study

Epidemiologic study

Family study; ADD vs. psychiatriccontrol vs. normal control;ADD+CD vs. ADD+OPD vs.ADD

aADDatrention deficit disorder, ADHD=attention deficit hyper-

activity disorder, ADDH=attention deficit disorder with hyper-activity, CDconduct disorder, OPDoppositional disorder.bMun

%�formation not provided.d�nge.eNumber of families rather than number of subjects.

BIEDERMAN, NEWCORN, AND SPRICH

Am J Psychiatry 148:5, May I 991 567

TABLE 1 (continued)

Instruments Used

C

Behavior checklists, achievement tests, peerrating scales

C

Rating scales

Clinical assessment, rating scalesStructured interviews, behavior checklists,

achievement tests

Clinical assessments, clinical interviews,WISC-R

Clinical rating sheets (ICD-9), factor scales

Structured interviews

Teacher ratings

Structured interviews, self-rating scales, psy-chiatric histories (DSM-III)

Teacher ratings, structured interview, atten-tional battery, achievement tests

Behavior checklists, psychiatric interviews

Semistructured interviews, behavior check-

lists, psychological testing

Structured interviews, behavior checklists

Clinical interviews, structured interviews

C

Structured interviews, statistical analysis ofindividual ADD and CD symptoms

Structured interviews, cognitive tests, behav-ior questionnaires

Behavior checklists, structured interviews

Achievement test, rating scales

Structured interviews, rating scales

Behavior and health checklists, intelligencetests, psychosocial assessment, police re-ports

Parental interview, behavior rating scales,cognitive tests

Behavior checklist, cognitive assessments,criminal records

Structured interviews, rating scales

Structured interviews

Structured interviews, behavior checklists,clinical diagnoses

Structured interviews, morbidity risk

Findings5

More perinatal events in ADD+CD; no differences on other measures of psychosocialdisadvantage or cognitive skills

H�gh intercorrelations for hyperactivity and conduct problem scale factors, similar corre-lation patterns for criterion variables; similar multiple regressions for combined andseparate factors

No differencesPositive correlation between hyperactive and aggressive symptoms; hyperactivity and ag-

gressive symptoms intertwinedNo differences in age, IQ, and family size; more school problems in ADDHAt follow-up hyperactive children still inattentive and impulsive; those with

hyperactivity+CD still inattentive, impulsive, aggressive, noncompliant, antisocial, andabusing alcohol

ADD with family history of antisocial diagnosis significantly higher on aggression, non-compliance, antisocial behavior, egocentricity; significantly higher rate of CD in sib-lings

CD had greater frequency of aggressive, antisocial, emotional, and psychosocial disrur-bances; hyperactive had greater frequency of hyperactivity and inattention

Full ADDH in 31% of hyperactive vs. 3% of control; CD and substance use disorders�gnificantly higher in hyperactive

ADDH ratings correlated with cognitive skills no differences on psychosocial disadvan-tage; inattention correlated with cognitive skills; CD and hyperactivity correlated withpsychosocial disadvantage

66 /o of hyperactive continued to have one or more disabling symptoms; 23% of hyper-active vs. 2.4% of control had antisocial personality disorder

2.3% had ADD; 3.6% had CD; 3.0% had ADD+CD; interdependence between ADDand CD

25% had high scores on hyperactivity and inattention; good response to stimulants; clas-sification of pervasive hyperactivity with inattention robust

Independence of inattentive and antisocial, defiant, CD dimensions

47% of ADD had CD and/or OPD; 35% of CD and/or OPD had ADD

64% of ADD had CD and/or OPD; 46% of ADD+CD/OPD relatives vs. 13% of ADDrelatives vs. 7% of control relatives had antisocial disorders

Aggressive symptoms differentiated hyperactive/minimal brain dysfunction boys on sev-eral measures; differentiation between hyperactivity+aggressive symptoms and hyper-activity valuable

Conditional probability of ADD in CD was 0.67; conditional probability of CD in ADDwas 0.30; ADD and CD are partially independent

52% had two or more diagnoses; 85% of CD had ADD; ADDH and CD are partiallyindependent

57% of ADD had CD and/or OPD; 47% of CD and/or OPD had ADD

Similar responses to methylphenidate in all three groups

Higher rates of aggression arrest, and imprisonment in fathers of ADHD+CD; familial-ity of ADD not reported

Highest rates of police contacts and self.reported delinquency in ADD+CD; 30.8% ofADD+CD vs. 3.4% of ADD vs. 20.7% of CD vs. 1.7% of remainder were multipleoffenders

Aggressive and nonaggressive ADHD similar in drug responses; aggressive had more im-paired family situataons

Hyperactivity and CD independently predictive of juvenile convictions; 4S.8% ofhyperactive+CD vs. 35% of CD vs. 23.5% of hyperactive vs. 12.6% with neitherwere convicted as juveniles

41% of ADDH vs. 20% of ADD had CD

For cohort 1, 68% of ADD vs. 13% of control had ADD and 4S% of ADD vs. 16% ofcontrol had CD; for cohort 2, 70% of ADD vs. 10% of control had ADD and 59%of ADD vs. 18% of control had CD

ADD and CD occurred together significantly often; ADD+CD seemed true hybriddisorder

Higher familial risk for ADD, antisocial disorders, and substance use disorder inADD+CD; earlier age at onset of ADD and highest rates of school dysfunction inADD+CD; ADD+CD had more virulent form of ADD OPD was familial (validity ofOPD); ADD+OPD was intermediate between ADD and ADD+CD (OPD may be sub-syndromal manifestation of CD)

COMORBIDITY OF ATfENTION DISORDER

568 Am J Psychiatry 148:5, May 1991

attention deficit hyperactivity disorder and conductdisorder are indistinguishable suggests that, given themeasurement and/or diagnosis of either attention def-icit hyperactivity disorder or conduct disorder, theidentification of the other yields no additional infor-mation. Proponents of this position point to the simi-larities between children with attention deficit hyper-activity disorder and children with conduct disorderfrequently reported in studies of correlates, outcome,and treatment responses (44, 50). Similarly, they pointto intercorrelations between symptoms of attentiondeficit hyperactivity disorder and symptoms of con-duct disorder (aggressive, disruptive, and noncompli-ant behaviors) often reported in factor-analytic studiesof children with behavioral disorders (Si, 52). In ad-dition, they cite a lack of substantial differences in psy-chosocial, neurodevelopmental, and perinatal factorsbetween children with attention deficit hyperactivitydisorder and children with conduct disorder (37).

Proponents of the independent position view atten-tion deficit hyperactivity disorder and conduct disor-der as either completely or partially independent. Sup-port for this position can be derived from studies thatcompared patterns of familial aggregation, cognitiveperformance, and outcome of children with attentiondeficit hyperactivity disorder with those of childrenwith attention deficit hyperactivity disorder plus con-duct disorder. In the studies of Loney et al. (53), symp-toms of hyperactivity and aggression were not highlycorrelated and showed different patterns of concurrentand predictive validity, suggesting that they were sep-arate dimensions. In those studies, the presence of con-duct disorder in childhood, whether associated withattention deficit hyperactivity disorder or not, was sig-nificantly correlated with aggressive behavior and de-linquency in adolescence (53), but childhood attentiondeficit hyperactivity disorder without conduct disorderwas correlated with cognitive and academic deficits(21, 32, 54). Similar findings emerged from a fol-low-up study in a nonclinical sample (55, 56). Otherstudies (21, 34, 38, 41, 45, 57, 58) have demonstratedthat children with attention deficit hyperactivity dis-order with an associated childhood-onset conduct dis-order have more serious clinical courses and pooreroutcomes than children with attention deficit hyperac-tivity disorder without conduct disorder.

Family studies have shown that childhood conductdisorder, but not attention deficit hyperactivity disor-der, is associated with parental antisocial behaviorsand alcoholism (6, 25, 38, 46, S4). Investigators havefound that the familial risk for attention deficit hyper-activity disorder and antisocial disorders is highestamong relatives of children with attention deficit hy-peractivity disorder with concomitant conduct disor-der (24, 28, 46, 54, 59). Several reports have alsoshown that a current or past history of attention deficithyperactivity disorder is frequently reported amongpatients with alcohol dependence (60-62) and drugaddiction (63, 64). Since follow-up studies of childrenand adolescents with the diagnosis of conduct disorder

are in agreement regarding the strong predictive powerof conduct disorder for future psychiatric disorders,social adjustment problems, antisocial personality, al-coholism, and criminality (58), it has been suggestedthat the delinquent behaviors and substance abuse of-ten reported in follow-up studies of boys with atten-tion deficit hyperactivity disorder (18, 65) may belinked to childhood antisocial disorders rather than tothe syndrome of attention deficit hyperactivity disor-der per se (4, 39, 45).

Two studies examining the response to stimulants ofchildren with attention deficit hyperactivity disorderwith and without associated conduct disorder (42, 44)found that the two groups of children showed similarpatterns of improvement with regard to symptoms ofattention deficit hyperactivity disorder. Although thesetwo studies cannot help resolve the debate regardingthe independence of attention deficit hyperactivity dis-order and conduct disorder, they support the clinicalrelevance of diagnosing both attention deficit hyperac-tivity disorder and conduct disorder when the disor-ders occur together.

Although debate continues as to whether attentiondeficit hyperactivity disorder is distinct from conductdisorder, the bulk of the evidence appears to indicatethat attention deficit hyperactivity disorder and con-duct disorder are at least partially independent dimen-sions and/or categories. Attention deficit hyperactivitydisorder and conduct disorder differ not only in theirdefining clinical features but also in external variablessuch as outcome (cognitive dysfunction for attentiondeficit hyperactivity disorder versus aggression, antiso-cial behaviors, substance abuse, and delinquency forconduct disorder), etiologic factors (familial aggrega-tion), and psychosocial and developmental correlates.Thus far, data from treatment studies have not re-solved the debate. There is increasing evidence thatchildren with attention deficit hyperactivity disorderplus conduct disorder appear to have a particularlysevere form of attention deficit hyperactivity disorder.Thus, subgrouping based on comorbidity with conductdisorder may be of potential value in determiningwhich children with attention deficit hyperactivity dis-order have a more serious prognosis and different fam-ily-genetic risk factors and require specialized compre-hensive therapeutic interventions.

COMORBIDITY WITH OPPOSITIONAL DEFIANTDISORDER

The nosologic status of oppositional defiant disorderand consequently that of attention deficit hyperactivitydisorder plus oppositional defiant disorder remains un-clear (66, 67). To date, only a few studies have gener-ated data on oppositional defiant disorder. Some ofthese have grouped oppositional defiant disorder andconduct disorder together into a single antisocial be-havioral category, making it difficult to draw conclu-sions about oppositional defiant disorder itself. The

BIEDERMAN, NEWCORN, AND SPRICH

Am J Psychiatry 1 48:5, May 1991 569

few studies available report an overlap of at least 35%between attention deficit hyperactivity disorder andoppositional defiant disorder, either alone or ‘cOrn-bined with conduct disorder, in both epidemiologic (2,3) and clinical (6, 46) studies of children and adoles-cents. Faraone et al. (46) recently demonstrated thatDSM-III oppositional disorder itself is also familialand that the risk for oppositional disorder among rel-atives of probands with attention deficit disorder plusoppositional disorder is three times greater than therisk among relatives of probands with attention deficitdisorder without oppositional disorder and nearly tentimes greater than the risk among relatives of normalcontrol subjects. These data provide some evidence forthe validity of DSM-III oppositional disorder.

In terms of severity of the clinical picture, the avail-able data suggest that children with attention deficithyperactivity disorder plus oppositional defiant disor-der may form an intermediate subgroup between thosewho have attention deficit hyperactivity disorder aloneand those with attention deficit hyperactivity disorderplus conduct disorder. For example, Faraone et al. (46)showed that although probands with DSM-III atten-tion deficit disorder plus oppositional disorder had ahigher rate of school dysfunction than those with at-tention deficit disorder alone, this rate was lower thanthat of subjects with attention deficit disorder plusconduct disorder. A similar pattern was observed inthe risk for attention deficit disorder and antisocialdisorders among relatives of probands: family mem-bers of probands with attention deficit disorder plusoppositional disorder were at higher risk for antisocialdisorders and attention deficit disorder than relativesof probands with attention deficit disorder alone but atlower risk than relatives of probands with attentiondeficit disorder plus conduct disorder. These findingsare consistent with the hypothesis that oppositionaldefiant disorder may be a subsyndromal manifestationof conduct disorder (unpublished 1985 paper by J.Loney).

COMORBIDITY WITH MOOD DISORDERS

Attention deficit hyperactivity disorder and mooddisorders have been found to occur together in 15% to75% of cases in both epidemiologic (2, 3) and clinical(6, 68-71) samples of children and adolescents (table2). Some investigators, however, have not found high-er-than-expected rates of mood disorders in childrenwith attention deficit hyperactivity disorder (10, 18,43, 72). In clinical samples, the association betweenattention deficit hyperactivity disorder and mood dis-orders has been reported in studies of children withnonbipolar major depression and dysthymia (75),studies of adolescents with bipolar disorder (80), andstudies of children with attention deficit hyperactivitydisorder (6, 69, 73, 77). Studies of high-risk children ofparents with mood disorders have found high rates ofattention deficit hyperactivity disorder in these chil-

dren (78, 79; unpublished 1989 paper by H. Orva-schel), and family studies of children with attentiondeficit hyperactivity disorder have found a significantlyhigher rate of mood disorders in probands with atten-tion deficit hyperactivity disorder and in their first-degree relatives than in normal control children andtheir first-degree relatives (74, 76). Studies of adoptedchildren with the diagnosis of attention deficit hyper-activity disorder found higher rates of major depres-sive disorder in the biological relatives of these chil-dren than in their adoptive relatives and the biologicalrelatives of control subjects (82). Case reports havedescribed individuals with childhood histories of atten-tion deficit hyperactivity disorder who developed ma-jor affective disorders in later years (83). It is doubtfulthat the comorbidity of attention deficit hyperactivitydisorder and mood disorders can be explained by as-certainment bias because high levels of comorbidity ofthese disorders have also been found in culturally andregionally diverse population-based epidemiologic sam-ples (2, 3, 5).

Findings reported by Biederman et al. (84) supportthe hypothesis that DSM-III attention deficit disorderand major depressive disorder share common familialvulnerabilities. Familial risk analyses revealed the fol-lowing: 1) the risk for major depressive disorderamong the relatives of probands with attention deficitdisorder was significantly higher than the risk amongrelatives of normal comparison children, 2) the risk formajor depressive disorder was the same among therelatives of probands with and without major depres-sive disorder and significantly higher in both groupsthan among the relatives of normal control children,and 3) the two disorders did not cosegregate withinfamilies. These findings are consistent with the hypoth-esis that attention deficit disorder and major depressivedisorder represent different expressions of the sameetiologic factors responsible for the manifestation ofattention deficit disorder. The reasons why the sharedgenotype may have differing phenotypic expressionssuch as attention deficit disorder, major depressive dis-order, or attention deficit disorder plus major depres-sive disorder remain unknown.

Follow-up data for children with attention deficithyperactivity disorder as well as for children with ma-jor depressive disorder (85, 86) strongly suggest thatalthough these disorders are individually associatedwith substantial long-term psychiatric morbidity, theiroccurrence together may be associated with a particu-larly poor outcome. In a study that evaluated predic-tors of suicide in adolescents, Brent et al. (87) reportedthat adolescents who committed suicide had higherrates of bipolarity and attention deficit hyperactivitydisorder than did those who attempted suicide. Thus,the occurrence together of attention deficit hyperactiv-ity disorder and mood disorder is suggestive of a sub-group of children with attention deficit hyperactivitydisorder at higher risk for greater psychiatric morbid-ity and disability (81) and perhaps at higher risk forsuicide than other children with attention deficit hy-

TABLE 2. Representative Studies of Comorbid Attention Deficft Hyperactivity Disorder and Depression

Subjects

AgeAuthor Year (years) Sex N

Type of StudyType and/or Comparisona

Stewart and Morrison(72)

Staton andBrumback (68)

Bohline (73)

Gittelman et al. (18)

Weiss et al.(10)

Anderson er al. (2)

Biederman et al. (74)

1973

1981

1985

1985

1985

1987

1987

Children M, F

5-12” M, F

6-11b M,F

16�23L� M

2l-33�’ M, F

11” M,F

6-17” M,F

6�l7L�

4-1&’

Alessi and Magen 1988(75)

Biederman et al. (76) (inpress)

Bird ct al. (3) 1988

Brown et al. (77) 1988

Jensen er al. (70) 1988

Keller et al. (78) 1988

1988 6-17b M, FOrvaschel et al. (79)

Strober et al. (80)

Lahey and Carlson(unpublished)

Mannuzza et al. (4)

Retrospective assessment of course

1988

1989 6-13b

Weinberg et al. (81) 1989

Woolston et al.(71) 1989

C

1989 16-23b M 372 Clinically referred; control

COMORBIDITY OF A1TENTION DISORDER

570 Am J Psychiatry 1 48:5, May 1991

135 Clinically referred

178 Referred for schoolproblems

108 Referred for special educa-tion

201 Referred for hyperactivity;normal control

102 Referred hyperactive andnormal control

792 Nonreferred; subset of 53given diagnosis of ADD

42C Clinically referred forADD and nonreferredcontrol

_C C 160 Clinically referred forMDD, dysthymia, orother diagnosis

Referred; pediatric controlM,F 99e

M,F 386 Probability sample frompopulation of PuertoRico

6-12” M, F 1 16e Referred; matched control

9-1&’ M 35 Referred outpatients andcontrol

6-19k’ M, F 275 Mixture of offspring ofMDD parents and com-munity sample of MDDand non-MDD parents

_C Children of referred unipo-lar parents and normalcontrol parents

M, F 81 lnpatients

M,F 103

6-15b M, F 227 All students in school for

children with learningdisabilities

4-14” M, F 35 Inpatients

Family study; biological ADD vs.adopted ADDv5. control

ADD vs. no ADD

Prospective longitudinal follow-upstudy; hyperactive vs. control

Prospective longitudinal follow-upstudy

Epidemiologic study

Family study

Examination of comorbid disorders

Family study; ADD+MDD vs.ADD vs. control

Two-stage epidemiologic study

Family study; ADD vs. no ADD

MDD vs. ADDH vs. control

High-risk study; MDD vs. control

Family study; bipolar I vs. schizo-phrenia

Review; ADD vs. ADDH

Follow-up study

ADD+MDD vs. ADD vs. MDD vs.chronic mood disturbance vs. nobehavioral condition

Psychiatric assessments

aADDattention deficit disorder, ADHD=attention deficit hyper-

activity disorder, ADDH=artention deficit disorder with hyper-activity, CD=conduct disorder, MDD=major depressive disorder,OPD=oppositional disorder.

peractivity disorder and adolescents without such co-morbid disorders.

COMORBIDITY WITH ANXIETY DISORDERS

Epidemiologic (2, 3) and clinical samples of childrenwith anxiety disorders (88) and children with attentiondeficit hyperactivity disorder (6, 43, 69, 71, 89) havefound a comorbid association between attention deficithyperactivity disorder and anxiety disorders of ap-

bRange.Clnformation not provided.dMeaneNumber of families rather than number of subjects.

proximately 25% (table 3). Investigators have alsonoted higher rates of attention deficit hyperactivity dis-order in children of parents with anxiety disordersthan in children of comparison groups (91). Lahey etal. (43, 90) noted that children with a DSM-III diag-nosis of attention deficit disorder without hyperactiv-

ity had higher rates of anxiety disorders than childrenwith attention deficit hyperactivity disorder. A recentinvestigation of the familial interrelationship betweenattention deficit hyperactivity disorder and anxiety dis-orders (92) provided evidence for an association be-

Clinical assessments

Questionnaires

Structured interviews

Structured interviews, self-rating scales, psy-chiatric histories (DSM-III)

Structured interviews, behavior checklists

Structured interviews

Structured interviews

Behavior checklists, structured interviews

Depression inventory

Rating scales, structured interviews

Structured interviews

_C High rates of MDD and ADD in children of MDD parents

C

No case of current major depression in ADD; lifetime (since age 13) prevalence of MDDnot significantly different between ADD and control

ADD+MDD had most behavioral problems

32% had ADHD with dysthymia

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Am J Psychiatry 148:5, May 1991 S71

TABLE 2 (continued)

Instruments Used Findings5

Interviews No significant differences in rates of bipolar and unipolar affective disorder

60% met criteria for MDD; 44% met criteria for hyperactivity; 75% of hyperactive hadMDD; 55% of MDD had hyperactivity

ADD more depressed than no ADD

3% of hyperactive vs. 2% of control had current affective disorder; 6% of hyperactivevs. 10% of control had history of affective disorder

More suicide attempts by hyperactive than control in year before follow-up; no signifi-cant differences in depression scores on self-rating scale

15% of ADD met criteria for depression and/or dysthymia; 57% of MDD met criteriafor ADD

32% of ADD and 27% of ADD relatives met criteria for MDD vs. none of control and6% of control relatives

Interviews 25% of ADD, 25% of CD, and 25% of anxious had MDD; 22% of ADD, 33% of CD,and 89% of anxious had dysthymia

26% of ADD probands had MDD; morbidity risks for ADD and MDD in ADD andADD+MDD differed significantly from control

19% of ADD met criteria for MDD; 30% of MDD met criteria for ADD

ADD and ADD parents were significantly more depressed than no ADD and no ADDparents

Rates of specific disorders not reported; significant symptom (externalizing) overlapbetween ADD and MDD; few ADD symptoms in MDD boys but high rates of exter-nalizing behaviors and impulsivity and low frustration tolerance (question of OPD);depressive symptoms commonly noted in ADDH boys (question of dysthymia)

14% had MDD; 87% had at least one MDD parent; 53% had anxiety, ADD, CD, orsubstance use disorder; 29% had two or more comorbid diagnoses; 45% with two ormore diagnoses had ADD

Structured interviews, RDC 24% of adolescent bipolar I probands had childhood history of ADDH; rate of ADDHin relatives not reported

9% of ADDH vs. 8% of ADD had MDD (n.s.)

Structured interviews

Standardized psychometric intelligence andachievement tests, semistructured inter-views

Clinical diagnoses, behavior checklists, intel-ligence tests

tween the two disorders. This study found 1) that therisk for anxiety disorders among the relatives of pa-tients with attention deficit hyperactivity disorder wassignificantly higher than the risk among relatives ofnormal comparison children, 2) that the risk for anx-iety disorders was significantly higher in relatives ofprobands with attention deficit hyperactivity disorderand anxiety disorders than in relatives of children withattention deficit hyperactivity disorder without anxietydisorders, and 3) that nonindependent transmission ofattention deficit hyperactivity disorder and anxiety dis-

orders within families could not be established. Thesefindings suggest that attention deficit hyperactivity dis-order and anxiety disorders transmit independently infamilies.

COMORBIDITY WiTH LEARNING DISABIL�ES

An overlap between attention deficit hyperactivitydisorder and learning disabilities has been consistentlyreported in the literature. The reported degree of over-

Author Year

Subjects

Type of Studyand/or Comparisona

Age(years) Sex N Type

Gittelman et al. (18)

Anderson et al. (2)

Lahey et al. (90)

Last et al. (88)

Munir et al. (69)

Sylvester et al. (91)

Bird et al. (3)

Mannuzza et al. (4)

1985

1987

1987

1987

1987

1987

1988

1989

16-23b

1 1C

6-13b

5_18b

516b

7��17b

4-16b

16-23b

M

M, F

M, F

M, F

M

M, F

M, F

M

201

792

63

73

42

91

386

372

Referred hyperactive andnormal control

Nonreferred; subset of 53given diagnosis of ADD

Clinically referred; givendiagnosis of ADD

Outpatients at anxietyclinic

Clinically referred; pediat-nc control

High-risk children of anx-ious, depressed, or con-trol parents

Probability sample frompopulation of PuertoRico

Clinically referred; control

Prospective longitudinal follow-upstudy; hyperactive vs. control

Epidemiologic study

ADDH vs. ADD

Assessment of comorbidity

Family study

Comparison of three structuredinterviews

Two-stage epidemiologic study

Follow-up study

Pliszka (89) 1989 M, F 79 Clinically referred Drug study

Woolston er al. (71)Biederman er al. (92)

19891991

4-14b

6-17bM, FM, F

35125

InpatientsClinically referred; pediat-

nc control

Psychiatric assessmentsFamily study; ADD vs. psychiatric

control vs. normal control

COMORBIDITY OF AUENTION DISORDER

572 Am J Psychiatry 1 48:5, May 1991

TABLE 3. Representative Studies of Comorbid Attention Deficit Hyperactivity Disorder and Anxiety

aADDattention deficit disorder, ADHD=attention deficit hyper-

activity disorder, ADDH=attention deficit disorder with hyperac-

tivity, CD=conduct disorder.

lap ranges from as low as 10% (57, 93) to as high as92% (94). This variability is most likely due to differ-ences in selection criteria, sampling, and measurementinstruments, as well as inconsistencies in the criteriaused to define both attention deficit hyperactivity dis-order and learning disabilities in different studies(95, 96). In addition to these inconsistencies in thedefinitions of learning disabilities and attention deficithyperactivity disorder, the academic dysfunction corn-monly associated with both conditions and the hetero-geneity of the learning disabilities have led to wide-spread confusion about these disorders.

Studies have consistently shown that children withattention deficit hyperactivity disorder perform morepoorly in school than control subjects, as evidenced bymore grade repetitions, poorer grades in academic sub-jects, more placement in special classes, and more tu-toring (94, 97-99). Findings also indicate that childrenwith attention deficit hyperactivity disorder performmore poorly than control subjects on standard meas-ures of intelligence and achievement (Si). Follow-up

studies have found that the academic and learningproblems of children with attention deficit hyperactiv-

ity disorder persist into adolescence and are associatedwith chronic underachievement and school failure (10,18). It is still unknown whether school failure in chil-dren with attention deficit hyperactivity disorder isrelated to the psychiatric picture of inattention andimpulsivity (attention deficit hyperactivity disorder),cognitive deficits (learning disabilities), a combinationof both factors (attention deficit hyperactivity disorder

bRange.Clnformation not provided.dMean

plus learning disabilities), or perhaps other factors

such as social disadvantage or demoralization and con-sequent decline in motivation (51).

The finding in some studies that learning disabilitiesare almost universally found among children with at-tention deficit hyperactivity disorder (94) has led someauthors to suggest that attention deficit hyperactivitydisorder and learning disabilities may be indistinguish-able (100). However, important differences exist in thedefining characteristics of both disorders. Although at-tention deficit hyperactivity disorder is a behavioralsyndrome with characteristic symptoms of inattentive-ness, impulsivity, and hyperactivity, learning disabili-ties refer to a group of cognitive disorders thought toreflect perceptual handicaps in one or more basic cog-nitive processes manifested as disorders of language,reading, writing and spelling, or arithmetic. Moreover,many children with attention deficit hyperactivity dis-order are achieving adequately, and not all childrenwith learning disabilities have attention deficit hyper-activity disorder, suggesting that the two disordersmay be independent but can overlap in some individ-uals (101).

In an attempt to clarify the nature of the associationbetween attention deficit hyperactivity disorder andlearning disabilities, researchers have begun to corn-pare subgroups of children with learning disabilities,attention deficit hyperactivity disorder, and attentiondeficit hyperactivity disorder plus learning disabilities(93, 102). Although this approach holds promise, moststudies have found few differences among subgroups.

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Am J Psychiatry 148:5, May 1991 573

TABLE 3 (continued)

Instruments Used Findings5

Structured interviews

Structured interviews, behavior checklists

None of hyperactive vs. 2% of control had current anxiety disorder; none of hyperactivevs. 3% of control had history of anxiety disorder

26% of ADD had anxiety; 24% of anxious had ADD

Structured interviews, behavior checklists 43% of ADD vs. 10% of ADDH had concurrent internalizing diagnosis

Semistructured interviews 16.7% of those with separation anxiety had ADD; 18.2% of overanxious had ADD

Structured interviews 27% of ADD vs. 15% of control had anxiety

Structured interviews, personalityinventories

Structured interviews, behavior checklists

33% with panic disorder parents vs. 6% with control parents had ADD according tochild report; 43% with panic disorder parents had panic disorder by parent report;40% with panic disorder parents had panic disorder by child report

8% of ADD had anxiety; 18% of anxious had ADD

Structured interviews

Clinical interviews, observational measures,memory tests

Behavior checklists, IQ testsStructured interviews

Current anxiety disorders rare in ADD; lifetime (since age 13) prevalence of anxiety dis-orders not significantly different between ADD and control

28% of ADHD had anxiety; ADHD+anxiety had significantly less CD than did ADHD;ADHD+anxiety had poorer response to methylphemdate than ADHD

61% had ADHD+anxiery30% of ADD vs. 15% of normal control had anxiety

For example, Halperin et al. (93) compared childrenwith attention deficit hyperactivity disorder plus learn-ing disabilities (reading disabilities) with children withonly attention deficit hyperactivity disorder to examinewhether children with both disorders constitute a dis-tinct subgroup. The authors interpreted their findingthat the two groups did not differ behaviorally or insociodemographic characteristics as giving minimalsupport to the usefulness of subgrouping attention def-icit hyperactivity disorder on the basis of the presenceof learning disabilities. In a study using a similar designand analytic approach, Ackerman et al. (102) alsofailed to find differences between children with comor-bid attention deficit hyperactivity disorder and learn-ing disabilities and children with attention deficit hy-peractivity disorder alone on measures of impulsivityand response to stimulants. It is important to stress,however, that although the children in these studies allshared the clinical features of attention deficit hyper-activity disorder, they may have differed in fundamen-tal ways determined by the presence of learning dis-abilities and its correlates. The identification of thesedifferences may have major clinical and educationalimportance because the two disorders require differentintervention approaches. Although more research isneeded to further evaluate the nature of the associationbetween attention deficit hyperactivity disorder andlearning disabilities, the subgroup of children withattention deficit hyperactivity disorder plus learningdisabilities deserves special clinical and educationalattention.

COMORBIDITY WITH OTHER DISORDERS

Attention deficit hyperactivity disorder is generallyconsidered to be three to four times more prevalent inmentally retarded children than in those with normalIQ scores (103-106). In a study that analyzed the typeof behavioral disturbance as a function of IQ (104),conduct disorder was found to be far more commonthan attention deficit hyperactivity disorder in boyswith IQs greater than SO, but attention deficit hyper-activity disorder and conduct disorder were equallyprevalent in children with IQs less than SO. In anotherstudy (103), attention deficit hyperactivity disorderwas found to be much more common in the educablementally retarded (IQ greater than SO) than in the gen-eral population. Russell (106) has noted that individ-uals with IQs less than SO may exhibit different typesof psychiatric disorders than those with milder mentalretardation. In addition, studies in which stimulanttreatment has been shown to be effective in childrenwith attention deficit hyperactivity disorder plus men-tal retardation have been conducted only in subjectswith mild mental retardation (107, 108). These dataare consistent with a definition of attention deficit hy-peractivity disorder that allows comorbidity with mildmental retardation but imposes an IQ cutoff belowwhich attention deficit hyperactivity disorder shouldnot be diagnosed. Since attention deficit hyperactivitydisorder appears to occur with increasing frequency inindividuals with mental retardation, more work needsto be done to evaluate whether attention and activity

COMORBIDITY OF A1TEN11ON DISORDER

574 Am J Psychiatry 148:5, May 1991

problems in the mentally retarded should be viewed asconstituting attention deficit hyperactivity disorder orwhether they are a consequence of having a low IQ.

Comorbidity of Tourette’s syndrome and attentiondeficit hyperactivity disorder has been well docu-mented. Approximately 60% of children and adoles-cents with Tourette’s syndrome have been shown tohave comorbid attention deficit hyperactivity disorder(13, 109-1 1 1). Because the prevalence of attentiondeficit hyperactivity disorder is much higher than thatof Tourette’s syndrome, only a small percentage ofchildren with attention deficit hyperactivity disorderwill have comorbid Tourette’s syndrome. Although thecomorbidity figures from these studies are in closeagreement, discrepant viewpoints have been proposedregarding their interpretation. Comings and Comings(109, 1 1 1) contended that there is a genetic relation-ship between Tourette’s syndrome and attention deficithyperactivity disorder and that a Tourette’s syndromegene (as yet unidentified) accounts for approximately10%-30% of attention deficit hyperactivity disorder.Conversely, Pauls et al. (13) disputed the conclusionthat attention deficit hyperactivity disorder andTourette’s syndrome are genetically related. Identi-fication of children at risk for the development ofTourette’s syndrome within the larger population ofindividuals with attention deficit hyperactivity disor-der has important practical implications because psy-chostimulant treatment has been associated with thedevelopment of Tourette’s syndrome in some studies(1 12) and may be contraindicated in children at highrisk for Tourette’s syndrome.

Comorbidity of attention deficit hyperactivity disor-der and borderline personality disorder has been de-scribed by Andrulonis et al. (1 13), who found that25% of a group of 106 borderline patients with IQsgreater than 80 had a current or past history of atten-tion deficit hyperactivity disorder and/or learning dis-abilities. Similarly, Bellak et al. (1 14-1 16) described agroup of subjects with impulsive behavior, learningproblems, mood lability, impaired judgment, disorga-nization, and intermittently poor reality testing whomthey referred to as having attention deficit hyperac-tivity disorder psychosis. Successful treatment of co-morbid attention deficit hyperactivity disorder andborderline personality with methyiphenidate (1 1 7) andimipramine (1 1 8) has been described in case reports.

CONCLUSIONS

There is increasing recognition that attention deficithyperactivity disorder is a heterogeneous disorder withconsiderable and varied comorbidity. The weight ofthe available literature indicates the frequent occur-rence together of conduct, mood, and anxiety disor-ders, as well as learning disabilities, with attention def-icit hyperactivity disorder in childhood, adolescence,and adulthood. The observed comorbidity does notappear to be either random or artifactual. Rather, spe-

cific patterns of symptoms and syndromes tend to oc-cur together in individuals and families. Current re-search findings have begun to suggest that subgroupsmight be delineated on the basis of patterns of comor-bidity. Recent family-genetic data suggest that atten-tion deficit hyperactivity disorder plus conduct disor-der may be a distinct subtype, that attention deficithyperactivity disorder and major depression may sharecommon familial vulnerabilities, and that attentiondeficit hyperactivity disorder and anxiety disordersmay be independently transmitted. Ongoing researchon attention deficit hyperactivity disorder and comor-bid learning disabilities as well as other comorbid dis-orders will determine the nature of their association.Subgroups of patients with attention deficit hyper-activity disorder may have different risk factors,clinical courses, neurobiology, and pharmacologicalresponses, so their proper identification may lead torefinements in prevention and treatment strategies. Al-though the high level of comorbidity within attentiondeficit hyperactivity disorder may lead to problems indifferential diagnosis, these difficulties do not invali-date the diagnosis of the disorder. Rather, further ex-amination of the patterns and structure of observedcomorbidity could help to revise and improve existingmethods of classification.

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