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ADHD
PATTERNS OF PSYCHIATRIC COMORBIDITY WITH ATTENTION-DEFICIT I HYPERACTIVITY DISORDER Steven R. Pliszka, MD
Children with attention deficit hyperactivity disorder (ADHD) may present to the clinician with a bewildering array of problems. Comorbidity of a psychiatric disorder is important because compared with a child with ADHD alone, an ADHD child with a comorbid condition may have a different clinical presentation, life course, and response to treatment. This article focuses on five major comorbid conditions that present challenges in clinical practice: (1) oppositional defiant disorder (ODD) or conduct disorder (CD); (2) learning disorders (LD); (3) anxiety disorders; (4) major depressive disorder (MOD); and (5) bipolar disorder (BD). There are, of course, a number of other conditions that may be comorbid with ADHD: tic disorders, neurologic disorders, medical conditions, and obsessive-compulsive and pervasive developmental disorders. These conditions, as well as more detail on the five conditions reviewed here, can be found in a recent text. 86 A great deal of data dealing with the effect of comorbidity on treatment outcome in children with ADHD has emerged from the MultiModality Treatment Study of ADHD (MTA). The MIA study differs from previous clinical trials in its greater sample size (579 patients), broader scope of treatment modalities, 14-month duration, intensity, diversity of treatment settings, and use of a long-term, nonmedication behavioral treatment. 2 It examined the effects of long-duration treatment
From the Division of Child and Adolescent Psychiatry, Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 9 •NUMBER 3 •JULY 2000
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in children randomly assigned to medication alone; behavioral treatments alone; a combination of medication and behavioral treatments; or to routine care in a community comparison group after assessment and referral. The medication treatment arm consisted of a medication management strategy, not the test of a single drug. Key factors in the treatment were regular monthly visits, monthly calls to the patient's teacher for monitoring ADHD symptoms in school, dosing three times daily, and supportive interventions. Because such a large number of subjects were enrolled, new data were generated on the rate of comorbidity in ADHD as well as the effect of comorbidity on treatment outcome. 100 ADHD AND DISRUPTIVE BEHAVIOR DISORDERS
About 50% of children with ADHD meet criteria for either ODD or CD. Age has a distinct effect on how frequently ADHD and CD cooccur. Almost all children younger than 12 years of age who meet criteria for ODD or CD will almost always meet criteria for ADHD. 87• 95 In adolescent samples, pure CD is more common, and only about one third of adolescent CD patients meet the criteria for ADHD. 95 These patients tend to be "late-onset" CD patients-they have no history of attentional or behavior problems as children but begin to engage in antisocial acts as teenagers. Generally, adolescent CD patients without a history of childhood ADHD are not candidates for stimulant treatment, but one may not uncommonly see an adolescent present with antisocial behavior who has a life-long history of untreated ADHD. Such an adolescent would be a good candidate for psychopharmacologic intervention. Physicians at times struggle over whether a child with ADHD is "really" just an oppositional or antisocial child who "does not want to pay attention." If a child meets criteria for ADHD, however, there is no objective way to know for sure if the ADHD is secondary to ODD. Thus, the physician should simply assess both sets of symptoms. The child may meet criteria for ADHD alone, ADHD and ODD with CD, or ODD with CD alone. Children in the first two groups are good candidates for psychopharmacologic intervention. Many features distinguish ADHD and ADHD-CD children. ADHDCD children come from families of lower socioeconomic status than ADHD-only children. 68 Teachers rate ADHD-CD children as having more symptoms of inattention and hyperactivity than ADHD children without CD, 87• 92 although these groups do not differ from each other on actual laboratory measures of activity level1°4 or on laboratory measures of attention and impulsivity. 58• 62, 92, 104 Although not different on laboratory measures of cognition, ADHD and ADHD-CD children do differ on measures of academic achievement. McGee et aF4 found that the rates of reading disorder (RD) in the ADHD, ADHD-CD, and control groups were 19%, 36%, and 7%, respectively. Moffit and Silva76 compared 13-year-old children in four groups: (1)
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ADHD; (2) ADHD with delinquency; (3) delinquency with no history of ADHD; and (4) controls. ADHD boys without delinquency were no different from controls on neuropsychologic measures, whereas the ADHD delinquents were impaired in terms of verbal skill, visual motor integration, and visuospatial skills. Impairments were most profound in the verbal area. ADHD children with poor verbal skills at 3 years of age were already showing reading problems at 5 years of age; these children were particularly prone to delinquency as teenagers.75 Medical and perinatal history does not distinguish ADHD from ADHD-CD children.5 • 73- 75• 87 ADHD-CD children have a much stronger family history of antisocial behavior in their first-degree relatives compared with children with ADHD alone. 14• 17• 40• 68 Indeed, for children who have ADHD alone, the rate of antisocial behavior in relatives does not exceed that of control children. Biederman et al1 4 examined the rate of psychiatric diagnosis among the relatives of a large sample of ADHD and ADHD-CD children. The risk for ADHD was the same in both groups of relatives, but the ADHD-CD children had an elevated number of relatives with CD (26%) compared with the ADHD-only group (13% ). Furthermore, relatives with CD also tended to have ADHD; that is, the two disorders cosegregated, indicating that ADHD-CD is a distinct familial subtype. This confirms an earlier study5 that also found that ADHD-CD children were more likely to have siblings who suffered from both ADHD and CD, whereas the siblings of children with ADHD alone only had hyperactivity. Because of the higher rate of family psychopathology, ADHD-CD children are exposed to a much greater level of psychosocial stress. The long-term outcomes of ADHD and ADHD-CD children are very different. August et al6 followed two samples of hyperactive children, one with pure hyperactivity and the other with high aggressivity. At 14 years of age, the hyperactive-aggressive group showed more antisocial and defiant behaviors, and whereas there were no cases of drug or alcohol abuse in the hyperactive group, 30% of the hyperactive-aggressive group had engaged in substance abuse. Loeber et al69 found that a third of ADHD-CD children had committed multiple crimes as teenagers, compared with only 3.4% of ADHD children without conduct disorder. Although ADHD by itself conveys some risk for adult antisocial behavior, it is when the ADHD child has a comorbid CD that the risk of adult antisocial personality and criminal conviction rises sharply.70• 71• 89 Many studies have compared ADHD and ADHD-CD children in terms of responsiveness to stimulant medication. When stimulant is compared with placebo in double-blind protocols, ADHD-CD children show an equally robust response to methylphenidate as do ADHD children without CD.8• 61• 83 ADHD-CD children not only show the same reductions in inattentiveness and hyperactivity as ADHD-only children, but antisocial behaviors themselves are reduced. 59 Overt aggressive behavior toward peers is clearly reduced when ADHD-CD children take stimulants.43• 77 Hinshaw et al54 found reductions in rates of stealing and vandalism when ADHD children were taking stimulants relative to
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placebo. Thus, stimulants should never be withheld from the ADHDCD child because it is assumed that the child's behavior is simply willtul. Aggressive outbursts may require adjunctive psychotropic medication, as noted in the subsequent section on BD. Because children with ADHD-CD come from more chaotic families, the physician often will need to refer to adjunctive psychosocial intervention. Behavioral interventions, as opposed to more open-ended therapies, may be need in this popula tion.79 ADHD AND LEARNING DISORDERS
Learning disorders (LD) are defined in various ways. In the first method, there is a discrepancy between the child's IQ and his or her performance on a standardized test of achievement. Research studies vary as to whether the child must be 1.5 or 2.0 standard deviations below the score as predicated by IQ to be classified as having a LD. Alternatively, a combined approach can be used: the child's achievement score must be more than 1.5 standard deviations below the level predicted by IQ, and the absolute standard score on the achievement must be below 85. This is a more conservative approach, but may underidentify highly intelligent persons with LD. As noted by Barkley/ when more liberal criteria are applied, 40% to 60% of ADHD children are identified with a LD, but using more rigid standards about 20% to 30% of ADHD children will be learning disabled in the areas of reading, spelling, or arithmetic.3, 7, 33, 37, 42, s3, 74, 91, 93 How are ADHD and ADHD with LD children different from each other? Most of the research had been conducted on ADHD children with a reading disorder (RD). When ADHD children with good reading ability are compared with RD children there is very little overlap of symptoms. That is, ADHD children are impaired on measures of impulse control, but perform as well as controls on phonologic tests. Conversely, dyslexic children whose Conners' ratings are in the normal range do well on attentional tests but perform poorly on language measures, confirming that ADHD and RD are distinct entities.63, 72, 80 Teachers perceive that ADHD-LD children have more severe inattention or impulsivity symptoms than those with ADHD alone. They also rate such children as having more CD symptoms. 102 Both ADHD and RD have strong genetic components but seem to be inherited independently. 41, 48, 49, s2, 91 In terms of treatment, children with RD alone do not show improved reading skills when treated with stimulants50 but ADHD-RD children do show increases in reading achievement test scores when their inattentiveness is successfully controlled with methylphenidate. 88 ADHD and ADHD-RD children also show an equally robust behavioral response to stimulants. 37 Some physicians are concerned that LD may masquerade as ADHD and fear that the school may refer for medication treatment to avoid doing a psychologic evaluation. In the ideal world, every child
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might have a full psychologic evaluation as part of an ADHD work-up, but given strained resources this often is not possible. If, however, there were a large population of children who met criteria for ADHD because of an underlying LD, one would expect LD comorbidity to predict stimulant nonresponse. As shown previously, this is not the case. Furthermore, it is possible that ADHD may cause a LD. If the child is inattentive for many years, he or she will clearly fall behind in his or her achievement. The child with ADHD who has low academic achievement can be adequately treated psychopharmacologically before psychometric examination is required. With control of the ADHD, the low achievement may resolve. If it does, evaluation of the child with ADHD symptoms under control will give a much clearer picture of any comorbid cognitive deficits. ADHD AND ANXIETY DISORDERS
About one quarter to one third of children with ADHD will meet criteria for an anxiety disorder, compared with 5% to 15% of the general population.21• 31 The MTA study found that 34% of children with ADHD met criteria for an anxiety disorder.99 Parents and children often differ on reports of anxiety- the parent states the child is anxious, but the child denies this, and vice versa. 20 Pliszka84 found that half of the ADHD children who met criteria for anxiety by their own report were not described as anxious by their parents, suggesting that as with depression, parents may often be unaware of their child's internalizing symptoms. Tannock96 compared two groups of children with ADHD with anxiety disorder: one group met criteria by child report, whereas in the other group the children denied anxiety but the parent reported anxiety symptoms in the child. Only the ADHD-anxiety children who themselves endorsed anxiety showed lower levels of self-confidence and impairment in daily activities. This suggests that it is the child, rather than the parent interview, that is more important in making the diagnosis of anxiety, but further research is needed to resolve the issue. How are ADHD children with and without comorbid anxiety different from each other? Pliszka83• 85 found that children with ADHD and anxiety were older at the time of presentation than children with ADHD alone. Biederman et al13 did not find differences in the rate of CD in ADHD and ADHD-anxiety children. In contrast Tannock96 found higher rates of CD among ADHD-anxiety children. Neither Tannock96 nor Biederman et al13 found differences between ADHD children with and without anxiety in terms of prevalence of LD. Although ADHD-anxiety and ADHD children were not found to be different in school performance, 13 ADHD-anxiety children reported more school problems than ADHDonly children.12 ADHD-anxiety children reported a wide variety of social difficulties beyond those reported by children with ADHD alone. Mothers of children with ADHD with anxiety reported higher levels of problems during pregnancy and developmental delays than mothers
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of children with ADHD alone. 96 Children with ADHD with anxiety experienced more stressful life events than ADHD-only children. 56• 96 Biederman et al1 3 found higher rates of divorce and separation among the families of AD HD-anxiety children (59%) compared with ADHDonly children (27% ). Biederman and colleagues 13• 14 have performed family studies to explore the pattern of inheritance of ADHD and anxiety. Compared with controls, the rate of anxiety disorders was elevated only in the relatives of ADHD-anxiety children, and not in the relatives of ADHD-only children. This is most consistent with the hypothesis that ADHD and anxiety are separate disorders inherited independently of each other. The most recent family study comparing ADHD and anxiety disorder children has confirmed this pattern.81 Seeking to determine predictors of stimulant response, Taylor et al 98 treated a heterogeneous group of boys with behavior problems with a double-blind placebo-controlled trial of methylphenidate. Boys who at baseline had more symptoms of depression or anxiety were least likely to respond to the drug. Pliszka85 treated 43 ADHD children (13 of whom had a comorbid anxiety) in a double-blind placebo-controlled crossover trial of methylphenidate. More than 80% of the nonanxious ADHD children were stimulant responders, whereas only 30% of the ADHDanxiety children were believed to benefit clearly from the drug. There were a number of placebo responders in the ADHD-anxiety group, whereas there were virtually no such responders in the nonanxious ADHD group. There was no evidence that the ADHD with anxiety children suffered any unusual side effects, nor did they appear to get more anxious. Of course, 30% of the ADHD-anxiety children did respond well to stimulants and continued treatment with methylphenidate, thus the study did not show that stimulants are absolutely contradicted in children with ADHD with anxiety. In contrast, Tannock et al 97 did find that side effects of stimulants appear greater in the ADHD-anxiety group relative to the ADHD-alone grou p . Furthermore, the ADHD children were followed while they received long-term methylphenidate treatment (over 12 months). ADHD-anxiety children not only had less behavioral improvement but what improvement there was tended to decline over time.96 Dupaul et al3 6 divided ADHD children into internalizers and noninternalizers based on the child's baseline Child Behavior Checklist score. Similar to Pliszka, 85 they found that ADHD children with comorbid internalizing symptoms had a less robust response to stimulants than nonanxious ADHD children. Buitelaar et al27 also found low anxiety to predict a good stimulant response in an unselected group of ADHD children. More recent work, however, has not confirmed these findings. Diamond et al3 4 found that anxious and nonanxious ADHD children had equally robust responses to methylphenidate in a short-term trial. In the recently completed MTA study more than 100 children received a double-blind placebo-controlled crossover trial of methylphenidate; one third of the children had comorbid anxiety disorders. Anxiety did not predict nonresponse to stimulant medication. The MTA study also
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showed that anxious ADHD children were more likely to benefit from a combination of medication and psychosocial treatment than nonanxious ADHD children. 100 The nonanxious ADHD children did not derive added benefit from the combination treatment over that provided by medication alone. Recently, specific serotonin reuptake inhibitors have been successful in open trials in treating children and adolescents with anxiety disorders. 22• 39 These medications can be combined with stimulants, as noted in the following discussion of depressive comorbidity. ADHD AND DEPRESSIVE DISORDERS
As with anxiety, reliability of parent and child report is lower for depressive symptoms than ODD-CD symptoms.ss, 82• 90 What should the clinician do if the child and parent reports of depression differ? For instance, the child may report he or she is depressed, feels guilty, and has trouble sleeping but deny all other problems. The parent may deny the child is depressed, but report concentration difficulties and loss of appetite. Should the total symptoms from the parent and child interview be combined to yield a diagnosis of MDD? This is what is done in most clinical practices, yet each clinician has developed a different method of doing it. Other studies rely only on the parent report, but if a parent says the child is depressed whereas the child strenuously denies depression, are we making a valid diagnosis? If we use the child report, then we must examine the issue as to how children at different developmental levels express their symptoms. In the Diagnostic and Statistical Manual (Fourth Edition), "irritable mood" can be used in the place of depressed mood to make a diagnosis of affective disorder in children, but children with ODD and CD often are irritable as part of their temper outbursts. Even children with ADHD alone may be emotionally labile as part of their impulsiveness. Given these issues, it is not surprising that studies have yielded highly discrepant results as to the prevalence of affective disorder in the ADHD population, with estimates ranging from 3% (which is not greater than that in the general population) to as high as 75%. 18 ADHD children in community samples show lower rates of MDD than those in clinical samples, suggesting a role for referral bias. 1• 14• 19 The MTA study found that 6% of their sample met criteria for a depressive disorder. 100 No study has directly compared ADHD children with and without MDD on specific clinical measures. Depressive symptoms generally have an onset after the ADHD symptoms, 11• 64 and the co-existence of ADHD and MDD does not appear to prolong the depressive episode or number of depressive episodes. 64• 66 ADHD is not associated with an increased risk of suicide attempts or suicide completion, 24• 26 it is the comorbidity of CD or substance abuse that increases such a risk. 2s How do clinicians distinguish between MDD in an ADHD child and "demoralization"? It is not uncommon to encounter children with
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ADHD who are dysphoric about the consequences of their ADHD behavior. Such children may appear depressed, but the dysphoria is shortlived and occurs following a disciplinary event. When asked if he or she is depressed, the child may state that he or she is sad because he or she was grounded for not turning in a homework assignment. Energy loss, guilt for things that are not the child's fault, suicidal ideation, or other neurovegetative signs are absent. A child should only be diagnosed with MOD if the depressed mood is present nearly every day for several hours and there are prominent neurovegetative signs. When MOD is clearly diagnosed, it follows its own independent course, persisting (if untreated) even if the ADHD symptoms remit. 16 In contrast, "demoralization" will resolve when the ADHD symptoms are treated successfully. Thus, if depressive symptoms continue after the child has responded to medication treatment of the ADHD, further treatment of the depression should be pursued. Depressed ADHD children and adolescents also are more likely to show a negative cognitive style, often found in adults with MDD. 9• 16 Compared with ADHD children without depression, ADHD-MDD youth have more negative views of themselves and more "depressogenic" attributions; 9 that is, they tend to view positive outcomes as related to chance, rather than their efforts, and negative outcomes are always viewed as personal failures. Biederman et al1 4 examined the prevalence of both ADHD and MOD in families of ADHD children with and without MOD. If the child had ADHD alone, the rates of ADHD and MOD in first-degree relatives were both elevated over the rates of a control group. A similar pattern was found in relatives of the ADHD-MDD children. The fact that nondepressed ADHD probands also had an increased risk of MOD in their relatives suggested some common familial links with ADHD and MOD. It should noted that these studies primarily used parent reports to make the diagnosis of MOD, and many of the ADHD children in the study were not past the age of risk for MOD. If they developed MOD in the future, this would move them (and their depressed relatives) into the ADHD-MDD group and reduce the prevalence of MOD in the relatives of the ADHD-only group. No studies have compared stimulant responsiveness in ADHD and ADHD-MDD subgroups, nor have there been any studies of differential response of these groups to psychotherapy. It might be assumed that tricyclic antidepressants would be the first choice for medication treatment; numerous studies have shown, however, that tricyclic antidepressants are not effective in the treatment of childhood MD0. 83 Recently, paroxetine was found to be superior to placebo in the treatment of adolescent MOD, but imipramine was not. 57 Fluoxetine was also better than placebo in a controlled trial in children and adolescents. 38 Fluoxetine was combined with methylphenidate (20 mg/ day) to treat 32 ADHD children and adolescents with comorbid mood disorders and C0. 44 No unusual side effects were encountered in this open trial, although controlled trials are needed. If a child with ADHD and MOD responds to stimulants but remains depressed, adding fluoxetine
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(10-20 mg/ day), sertraline (50-200 mg/ day), or paroxetine (10-30 mg/ day) may be beneficial. More detailed dosing guidelines for these medications can be found elsewhere. 67 ADHD AND BIPOLAR DISORDER
How prevalent is BD in children with ADHD? This topic has generated heated controversy and has grown out of the more general issue as to the prevalence of BD in children and adolescents. Epidemiologic studiesI, 4 , 32 have not found high rates of the disorder. Early studies did show that children diagnosed as manic have a high prevalence of symptoms of ADHD and other externalizing disorders,29 and there is a high rate of mania among ADHD children in institutional settings.IOI Thus part of this debate is influenced by referral bias. A primary care physician seeing primarily outpatient ADHD might go an entire career without encountering a case of BD, whereas a psychiatrist in a hospital or tertiary care setting might see children who meet criteria for mania on a weekly basis. Wozniak et al1°6 examined 262 clinically referred prepubertal children and found 43 that met criteria for mania; all but one of these children also met criteria for ADHD. Within this sample there were 164 cases of non-BD ADHD, thus the rate of mania in this sample of ADHD children was 16%. There were only two children with euphoric mania; 77% showed "extreme and persistent mania." Eighty-four percent showed "mixed mania" in which mania and MDD symptoms co-occurred. Compared with non-BD ADHD children, the comorbid group showed a higher rate of RD and lower Global Assessment of Functioning scores. They also had higher rates of other psychiatric disorders, including conduct, anxiety, and depressive disorders. Similar results emerged from a second sample of ADHD children studied by this group.Is Child Behavior Checklist scores of manic ADHD children were elevated over those of nonmanic ADHD children on nearly all subscales, but particularly on the Aggression subscale. ADHD-manic children were found to have higher rates of BD among their relatives, whereas the rate of BD in the relatives of nonmanic ADHD children did not exceed that of a control group.Is, 107 After screening many referrals, Geller et al46• 47 identified 60 prepubertal children with mania. Nearly all of these children had ADHD as well. The manic children were compared with 60 matched controls who had ADHD but no mood disorder. Factors that Geller et al46' 47 found most differentiated ADHD-manic from ADHD nonmanic patients were as follows: grandiosity (85% versus 6.7%), elated mood (87% versus 5%), racing thoughts (48 versus 0%), and hypersexuality (45% versus 8%). The results obtained by Geller et al46, 47 were largely consistent with those of the Massachusetts General Hospital (MGH)Is, Io6 group, with the exception that the Geller et al46' 47 group in St. Louis found higher rates of elated mood whereas the MGH group found primarily irritable mood.
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Not all investigators accept the results of the MGH and St. Louis groups, however. This disagreement has been aired recently. 10• 6 ° Klein et al 60 criticize the MGH group for not requiring distinct cycles of manic symptoms. They state that the MGH findings are inconsistent with the low rate of BO found in epidemiologic samples as well as the follow-up studies of ADHD children that do not show any cases of B0. 50• 103 Biederman10 replied that childhood-onset BO may well present differently from adult BO and such early onset cases may have severe, persistent mania. Geller et al46• 47 have argued from their data that childhood manic patients may have "ultraradian" cycles: that is, they may move in and out of mania within several hours. Wilens et al1°5 also argued that epidemiologic and early follow-up studies may well have missed more severely disturbed children because they were excluded from the studies. While the debate continues, there is no doubt that there are a subset of severely disturbed children with ADHD: they have very irritable mood and dangerous aggression, and are only partially responsive to stimulants. Whether they have a formal diagnosis of BO or not, mood stabilizers may be of benefit. Lithium is superior to placebo in adolescent B0. 45 Lithium also has been found to be superior to placebo in reducing aggressive behavior in the inpatient setting. 28 A combined approach, using both lithium and stimulants, may be necessary in the ADHD-CD child to treat the full range of both inattentive and aggressive symptoms. With proper monitoring, these drugs can be combined safely. 30 Divalproex sodium, found to be effective in adult mania, 23 has shown promise in adolescent mania, although no controlled trials have been performed.78 Even in the absence of clear-cut mania, divalproex sodium has been shown to reduce aggressive outbursts both in open35 and controlled trials. 94 Stimulants can be combined with divalproex sodium without difficulty. The decision as to whether to start stimulants or a mood stabilizer first in the ADHD-manic child is complex. Pliszka et al 86 provide extensive guidelines on this matter. CONCLUSIONS
A rich body of data has emerged demonstrating the association of ADHD with other psychiatric disorders. ADHD with CD clearly appears to be a distinct subtype, and although it responds well to stimulants in the short run, the long-term course is quite stormy. Learning disorders are independent of ADHD, and their co-occurrence does not appear to influence the child's response to stimulants. Anxiety disorders also seem to be independent of ADHD. When ADHD children are anxious, they show lower impulsiveness, although they are still impaired on this dimension relative to controls. Their response to stimulants may be poorer than that of children with ADHD alone, although recent data challenge this view. They may, however, be more responsive to a combined approach of medication and psychosocial intervention. The pat-
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tern with mood disorders is much less clear, and further research is needed to examine the prevalence of BD among ADHD children. Advances in neuroimaging and genetics may lead to a greater understanding of the comorbidity of ADHD with other psychiatric disorders.
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42. Frick PJ, Kamphaus RW, Lahey BB, et al: Academic underachievement and the disruptive behavior disorders. J Consult Clin Psychol 59:289-294, 1991 43. Gadow KD, Nolan EE, Sverd J, et al: Methylphenidate in aggressive-hyperactive boys: I. Effects on peer aggression in public school settings. JAm Acad Child Adolesc Psychiatry 29:710-718, 1990 44. Gammon GD, Brown TE: Fluoxetine and rnethylphenidate in combination for treatment of attention deficit and cornorbid depressive disorder. J Child Adolesc Psychopharrnacol 3:1-10, 1993 45. Geller B, Cooper TB, Sun K, et al: Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Arn Acad Child Adolesc Psychiatry 37:171-178, 1998 46. Geller B, Warner K, Williams M, et al: Prepubertal and young adolescent bipolarity versus ADHD: Assessment and validity using the WASH-U-KSADS, CBCL and TRF. J Affect Disord 51:93-100, 1998 47. Geller B, Williams M, Zimerman B, et al: Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms; grandiose delusion; ultra-rapid or ultraadian cycling. J Affect Disord 51:81-91, 1998 48. Gilger JW, Pennington BF, Defries JC: A twin study of the etiology of cornorbidity: Attention-deficit hyperactivity disorder and dyslexia. J Arn Acad Child Adolesc Psychiatry 31:343-348, 1992 49. Gillis JJ, Gilger JW, Pennington BF, et al: Attention deficit disorder in reading-disabled twins: Evidence for a genetic etiology. J Abnorrn Child Psycho! 20:303-315, 1992 50. Gittelman R, Mannuzza S, Shenker R, et al: Hyperactive boys almost grown up. I. Psychiatric status. Arch Gen Psychiatry 42:937- 947, 1985 51. Gittelman-Klein R, Klein DF: Methylphenidate effects in learning disabilities. Arch Gen Psychiatry 33:655-664, 1976 52. Goodman R, Stevenson J: A twin study of hyperactivity-I. An examination of hyperactivity scores and categories derived from Rutter teacher and parent questionnaires. J Child Psycho! Psychiatry 30:671-689, 1989 53. Halperin JM, Gittelman R, Klein DF, et al: Reading-disabled hyperactive children: A distinct subgroup of attention deficit disorder with hyperactivity? J Abnorrn Child Psycho! 12:1-14, 1984 54. Hinshaw SP, Heller T, McHale JP: Covert antisocial behavior in boys with attentiondeficit hyperactivity disorder: External validation and effects of rnethylphenidate. J Consult Clin Psycho! 60:274-281, 1992 55. Jensen P, Roper M, Fisher P, et al: Test-Retest reliability of the Diagnostic Interview Schedule for Children. (DISC 2.1). Arch Gen Psychiatry 52:61-71, 1995 56. Jensen PS, Shervette RE, Xenakis SN, et al: Anxiety and depressive disorders in attention deficit disorder with hyperactivity: New findings. Am JPsychiatry 150:12031209, 1993 57. Keller MB, Ryan ND, Birmaher B, et al: Paroxetine and irnipramine in the treatment of adolescent depression. New Research Program Abstracts. Presented at the Annual Meeting of the American Psychiatric Association, Toronto, May 9-12, 1998 58. Klee SH, Garfinkel BD: The computerized continuous performance task: A new measure of inattention. JAbnorrn Child Psychol 11:487-495, 1983 59. Klein RG: Clinical efficacy of rnethylphenidate in children and adolescents. Encephale 19:89-93, 1993 60. Klein RG, Pine DS, Klein DF: Resolved: Mania is mistaken for for the ADHD in prepubertal children, negative. J Am Acad Child Adolesc Psychiatry 37:1093-1096, 1998 61. Klorrnan R, Brumaghim JI, Salzman LF, et al: Comparative effects of rnethylphenidate on attention-deficit hyperactivity disorder with and without aggressive I noncornpliant features. Psychopharrnacol Bull 25:109-113, 1989 62. Koriath U, Gualtieri CT, Van Bourogdien ME, et al: Construct validity of clinical diagnosis in pediatric psychiatry: Relationship among measures. J Arn Acad Child Psychiatry 24:429-436, 1985 63. Korkrnan M, Pesonen AE: A comparison of neuropsychological test profiles of chi!-
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85. Pliszka SR: Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Arn Acad Child Adolesc Psychiatry 28:882-887, 1989 86. Pliszka SR, Carlson CL, Swanson JM: ADHD with Cornorbid Disorders: Clinical Assessment and Management. New York, Guilford Press, 1999 87. Reeves JC, Werry JS, Elkind GS, et al: Attention deficit, conduct, oppositional, and anxiety disorders in children. II. Clinical characteristics. J Arn Acad Child Adolesc Psychiatry 26:144-155, 1987 88. Richardson E, Kupietz SS, Winsberg BG, et al: Effects of rnethylphenidate dosage in hyperactive reading-disabled children: II. Reading achievement. J Arn Acad Child Adolesc Psychiatry 27:78-87, 1988 89. Satterfield J, Swanson J, Schell A, et al: Prediction of antisocial behavior in attentiondeficit hyperactivity disorder boys from aggression/ defiance scores. JArn Acad Child Adolesc Psychiatry 33:185-190, 1994 90. Schwab-Stone M, Fisher P, Piacentini J, et al: The Diagnostic Interview Schedule for Children-Revised Version (DISC-R): II. Test-retest reliability. J Arn Acad Child Adolesc Psychiatry 32:651-657, 1993 91. Sernrud-Clikernan M, Biederman J, Sprich-Buckrninster S, et al: Cornorbidity between ADDH and learning disability: A review and report in a clinically referred sample. J Arn Acad Child Adolesc Psychiatry 31:439-448, 1992 92. Shapiro SK, Garfinkel BD: The occurrence of behavior disorders in children: The interdependence of attention deficit disorder and conduct disorder. J Arn Acad Child Psychiatry 25:809-819, 1986 93. Shaywitz SE, Shaywitz BE: Attention deficit disorder: Current perspectives. In Kavanaugh JF, Truss TJ (eds): Learning Disabilities: Proceedings of the National Conference. Parkton, MD, York Press, 1988, pp 369-523 94. Steiner H, Matthews Z: Randomized clinical trial of depakote in delinquents. Presented at the 44th Annual of Meeting of the American Academy of Child and Adolescent Psychiatry, Toronto, October 14-19, 1997 95. Szatrnari P, Boyle M, Offord DR: ADDH and conduct disorder: Degree of diagnostic overlap and differences among correlates. J Arn Acad Child Adolesc Psychiatry 28:865- 872, 1989 96. Tannock R: Attention deficit disorders with anxiety disorders. In Brown TE (ed): Subtypes of Attention Deficit Disorders in Children, Adolescents and Adults. New York, American Psychiatric Press, 1994 97. Tannock R, Ickowicz A, Schachar R: Effects of cornorbid anxiety disorder on stimulant response in children with ADHD. Presented at the 38th annual meeting of the American Academy of Child and Adolescent Psychiatry, San Francisco, October 16-20, 1991 98. Taylor E, Schachar R, Thorley G, et al: Which boys respond to stimulant medication? A controlled trial of methylphenidate in boys with disruptive behavior. Psychol Med 17:121-143, 1987 99. The MTA Cooperative Group: A 14-rnonth randomized clinical trial of treatment strategies for Attention Deficit Hyperactivity Disorder. Arch Gen Psychiatry 56:10731087, 2000 100. The MTA Cooperative Group: Moderators and mediators of treatment response for children with ADHD: The MTA study. Arch Gen Psychiatry 56:1088-1096, 2000 101. Thompson LL, Riggs PD, Mikulich SK, et al: Contribution of ADHD symptoms to substance problems and delinquency in conduct-disordered adolescents. J Abnorrn Child Psychol 24:325- 347, 1996 102. Tirosh E, Berger J, Cohen-Ophir M, et al: Learning disabilities with and w ithout attention-deficit hyperactivity disorder: Parents' and teachers' perspectives. J Child Neural 13:270- 276, 1998 103. Weiss G, Hechtrnan L, Trokenberg L: Hyperactive Children Grown Up: Empirical Findings and Theoretical Considerations. New York, Guilford Press, 1986 104. Werry JS, Elkind GS, Reeves JC: Attention deficit, conduct, oppositional, and anxiety disorders in children: III. Laboratory differences. J Abnorrn Child Psycho! 15:409428, 1987 105. Wilens TE, Biederman J, Mick E, et al: Attention deficit hyperactivity disorder
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Address reprint requests to Steven R. Pliszka, MD UTHSCSA, Department of Psychiatry 7703 Floyd Curl Drive San Antonio, TX 78229- 3900 e-mail: [email protected]
ADHD
PATTERNS OF PSYCHIATRIC COMORBIDITY WITH ATTENTION-DEFICIT I HYPERACTIVITY DISORDER Steven R. Pliszka, MD
Children with attention deficit hyperactivity disorder (ADHD) may present to the clinician with a bewildering array of problems. Comorbidity of a psychiatric disorder is important because compared with a child with ADHD alone, an ADHD child with a comorbid condition may have a different clinical presentation, life course, and response to treatment. This article focuses on five major comorbid conditions that present challenges in clinical practice: (1) oppositional defiant disorder (ODD) or conduct disorder (CD); (2) learning disorders (LD); (3) anxiety disorders; (4) major depressive disorder (MOD); and (5) bipolar disorder (BD). There are, of course, a number of other conditions that may be comorbid with ADHD: tic disorders, neurologic disorders, medical conditions, and obsessive-compulsive and pervasive developmental disorders. These conditions, as well as more detail on the five conditions reviewed here, can be found in a recent text. 86 A great deal of data dealing with the effect of comorbidity on treatment outcome in children with ADHD has emerged from the MultiModality Treatment Study of ADHD (MTA). The MIA study differs from previous clinical trials in its greater sample size (579 patients), broader scope of treatment modalities, 14-month duration, intensity, diversity of treatment settings, and use of a long-term, nonmedication behavioral treatment. 2 It examined the effects of long-duration treatment
From the Division of Child and Adolescent Psychiatry, Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
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in children randomly assigned to medication alone; behavioral treatments alone; a combination of medication and behavioral treatments; or to routine care in a community comparison group after assessment and referral. The medication treatment arm consisted of a medication management strategy, not the test of a single drug. Key factors in the treatment were regular monthly visits, monthly calls to the patient's teacher for monitoring ADHD symptoms in school, dosing three times daily, and supportive interventions. Because such a large number of subjects were enrolled, new data were generated on the rate of comorbidity in ADHD as well as the effect of comorbidity on treatment outcome. 100 ADHD AND DISRUPTIVE BEHAVIOR DISORDERS
About 50% of children with ADHD meet criteria for either ODD or CD. Age has a distinct effect on how frequently ADHD and CD cooccur. Almost all children younger than 12 years of age who meet criteria for ODD or CD will almost always meet criteria for ADHD. 87• 95 In adolescent samples, pure CD is more common, and only about one third of adolescent CD patients meet the criteria for ADHD. 95 These patients tend to be "late-onset" CD patients-they have no history of attentional or behavior problems as children but begin to engage in antisocial acts as teenagers. Generally, adolescent CD patients without a history of childhood ADHD are not candidates for stimulant treatment, but one may not uncommonly see an adolescent present with antisocial behavior who has a life-long history of untreated ADHD. Such an adolescent would be a good candidate for psychopharmacologic intervention. Physicians at times struggle over whether a child with ADHD is "really" just an oppositional or antisocial child who "does not want to pay attention." If a child meets criteria for ADHD, however, there is no objective way to know for sure if the ADHD is secondary to ODD. Thus, the physician should simply assess both sets of symptoms. The child may meet criteria for ADHD alone, ADHD and ODD with CD, or ODD with CD alone. Children in the first two groups are good candidates for psychopharmacologic intervention. Many features distinguish ADHD and ADHD-CD children. ADHDCD children come from families of lower socioeconomic status than ADHD-only children. 68 Teachers rate ADHD-CD children as having more symptoms of inattention and hyperactivity than ADHD children without CD, 87• 92 although these groups do not differ from each other on actual laboratory measures of activity level1°4 or on laboratory measures of attention and impulsivity. 58• 62, 92, 104 Although not different on laboratory measures of cognition, ADHD and ADHD-CD children do differ on measures of academic achievement. McGee et aF4 found that the rates of reading disorder (RD) in the ADHD, ADHD-CD, and control groups were 19%, 36%, and 7%, respectively. Moffit and Silva76 compared 13-year-old children in four groups: (1)
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ADHD; (2) ADHD with delinquency; (3) delinquency with no history of ADHD; and (4) controls. ADHD boys without delinquency were no different from controls on neuropsychologic measures, whereas the ADHD delinquents were impaired in terms of verbal skill, visual motor integration, and visuospatial skills. Impairments were most profound in the verbal area. ADHD children with poor verbal skills at 3 years of age were already showing reading problems at 5 years of age; these children were particularly prone to delinquency as teenagers.75 Medical and perinatal history does not distinguish ADHD from ADHD-CD children.5 • 73- 75• 87 ADHD-CD children have a much stronger family history of antisocial behavior in their first-degree relatives compared with children with ADHD alone. 14• 17• 40• 68 Indeed, for children who have ADHD alone, the rate of antisocial behavior in relatives does not exceed that of control children. Biederman et al1 4 examined the rate of psychiatric diagnosis among the relatives of a large sample of ADHD and ADHD-CD children. The risk for ADHD was the same in both groups of relatives, but the ADHD-CD children had an elevated number of relatives with CD (26%) compared with the ADHD-only group (13% ). Furthermore, relatives with CD also tended to have ADHD; that is, the two disorders cosegregated, indicating that ADHD-CD is a distinct familial subtype. This confirms an earlier study5 that also found that ADHD-CD children were more likely to have siblings who suffered from both ADHD and CD, whereas the siblings of children with ADHD alone only had hyperactivity. Because of the higher rate of family psychopathology, ADHD-CD children are exposed to a much greater level of psychosocial stress. The long-term outcomes of ADHD and ADHD-CD children are very different. August et al6 followed two samples of hyperactive children, one with pure hyperactivity and the other with high aggressivity. At 14 years of age, the hyperactive-aggressive group showed more antisocial and defiant behaviors, and whereas there were no cases of drug or alcohol abuse in the hyperactive group, 30% of the hyperactive-aggressive group had engaged in substance abuse. Loeber et al69 found that a third of ADHD-CD children had committed multiple crimes as teenagers, compared with only 3.4% of ADHD children without conduct disorder. Although ADHD by itself conveys some risk for adult antisocial behavior, it is when the ADHD child has a comorbid CD that the risk of adult antisocial personality and criminal conviction rises sharply.70• 71• 89 Many studies have compared ADHD and ADHD-CD children in terms of responsiveness to stimulant medication. When stimulant is compared with placebo in double-blind protocols, ADHD-CD children show an equally robust response to methylphenidate as do ADHD children without CD.8• 61• 83 ADHD-CD children not only show the same reductions in inattentiveness and hyperactivity as ADHD-only children, but antisocial behaviors themselves are reduced. 59 Overt aggressive behavior toward peers is clearly reduced when ADHD-CD children take stimulants.43• 77 Hinshaw et al54 found reductions in rates of stealing and vandalism when ADHD children were taking stimulants relative to
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placebo. Thus, stimulants should never be withheld from the ADHDCD child because it is assumed that the child's behavior is simply willtul. Aggressive outbursts may require adjunctive psychotropic medication, as noted in the subsequent section on BD. Because children with ADHD-CD come from more chaotic families, the physician often will need to refer to adjunctive psychosocial intervention. Behavioral interventions, as opposed to more open-ended therapies, may be need in this popula tion.79 ADHD AND LEARNING DISORDERS
Learning disorders (LD) are defined in various ways. In the first method, there is a discrepancy between the child's IQ and his or her performance on a standardized test of achievement. Research studies vary as to whether the child must be 1.5 or 2.0 standard deviations below the score as predicated by IQ to be classified as having a LD. Alternatively, a combined approach can be used: the child's achievement score must be more than 1.5 standard deviations below the level predicted by IQ, and the absolute standard score on the achievement must be below 85. This is a more conservative approach, but may underidentify highly intelligent persons with LD. As noted by Barkley/ when more liberal criteria are applied, 40% to 60% of ADHD children are identified with a LD, but using more rigid standards about 20% to 30% of ADHD children will be learning disabled in the areas of reading, spelling, or arithmetic.3, 7, 33, 37, 42, s3, 74, 91, 93 How are ADHD and ADHD with LD children different from each other? Most of the research had been conducted on ADHD children with a reading disorder (RD). When ADHD children with good reading ability are compared with RD children there is very little overlap of symptoms. That is, ADHD children are impaired on measures of impulse control, but perform as well as controls on phonologic tests. Conversely, dyslexic children whose Conners' ratings are in the normal range do well on attentional tests but perform poorly on language measures, confirming that ADHD and RD are distinct entities.63, 72, 80 Teachers perceive that ADHD-LD children have more severe inattention or impulsivity symptoms than those with ADHD alone. They also rate such children as having more CD symptoms. 102 Both ADHD and RD have strong genetic components but seem to be inherited independently. 41, 48, 49, s2, 91 In terms of treatment, children with RD alone do not show improved reading skills when treated with stimulants50 but ADHD-RD children do show increases in reading achievement test scores when their inattentiveness is successfully controlled with methylphenidate. 88 ADHD and ADHD-RD children also show an equally robust behavioral response to stimulants. 37 Some physicians are concerned that LD may masquerade as ADHD and fear that the school may refer for medication treatment to avoid doing a psychologic evaluation. In the ideal world, every child
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might have a full psychologic evaluation as part of an ADHD work-up, but given strained resources this often is not possible. If, however, there were a large population of children who met criteria for ADHD because of an underlying LD, one would expect LD comorbidity to predict stimulant nonresponse. As shown previously, this is not the case. Furthermore, it is possible that ADHD may cause a LD. If the child is inattentive for many years, he or she will clearly fall behind in his or her achievement. The child with ADHD who has low academic achievement can be adequately treated psychopharmacologically before psychometric examination is required. With control of the ADHD, the low achievement may resolve. If it does, evaluation of the child with ADHD symptoms under control will give a much clearer picture of any comorbid cognitive deficits. ADHD AND ANXIETY DISORDERS
About one quarter to one third of children with ADHD will meet criteria for an anxiety disorder, compared with 5% to 15% of the general population.21• 31 The MTA study found that 34% of children with ADHD met criteria for an anxiety disorder.99 Parents and children often differ on reports of anxiety- the parent states the child is anxious, but the child denies this, and vice versa. 20 Pliszka84 found that half of the ADHD children who met criteria for anxiety by their own report were not described as anxious by their parents, suggesting that as with depression, parents may often be unaware of their child's internalizing symptoms. Tannock96 compared two groups of children with ADHD with anxiety disorder: one group met criteria by child report, whereas in the other group the children denied anxiety but the parent reported anxiety symptoms in the child. Only the ADHD-anxiety children who themselves endorsed anxiety showed lower levels of self-confidence and impairment in daily activities. This suggests that it is the child, rather than the parent interview, that is more important in making the diagnosis of anxiety, but further research is needed to resolve the issue. How are ADHD children with and without comorbid anxiety different from each other? Pliszka83• 85 found that children with ADHD and anxiety were older at the time of presentation than children with ADHD alone. Biederman et al13 did not find differences in the rate of CD in ADHD and ADHD-anxiety children. In contrast Tannock96 found higher rates of CD among ADHD-anxiety children. Neither Tannock96 nor Biederman et al13 found differences between ADHD children with and without anxiety in terms of prevalence of LD. Although ADHD-anxiety and ADHD children were not found to be different in school performance, 13 ADHD-anxiety children reported more school problems than ADHDonly children.12 ADHD-anxiety children reported a wide variety of social difficulties beyond those reported by children with ADHD alone. Mothers of children with ADHD with anxiety reported higher levels of problems during pregnancy and developmental delays than mothers
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of children with ADHD alone. 96 Children with ADHD with anxiety experienced more stressful life events than ADHD-only children. 56• 96 Biederman et al1 3 found higher rates of divorce and separation among the families of AD HD-anxiety children (59%) compared with ADHDonly children (27% ). Biederman and colleagues 13• 14 have performed family studies to explore the pattern of inheritance of ADHD and anxiety. Compared with controls, the rate of anxiety disorders was elevated only in the relatives of ADHD-anxiety children, and not in the relatives of ADHD-only children. This is most consistent with the hypothesis that ADHD and anxiety are separate disorders inherited independently of each other. The most recent family study comparing ADHD and anxiety disorder children has confirmed this pattern.81 Seeking to determine predictors of stimulant response, Taylor et al 98 treated a heterogeneous group of boys with behavior problems with a double-blind placebo-controlled trial of methylphenidate. Boys who at baseline had more symptoms of depression or anxiety were least likely to respond to the drug. Pliszka85 treated 43 ADHD children (13 of whom had a comorbid anxiety) in a double-blind placebo-controlled crossover trial of methylphenidate. More than 80% of the nonanxious ADHD children were stimulant responders, whereas only 30% of the ADHDanxiety children were believed to benefit clearly from the drug. There were a number of placebo responders in the ADHD-anxiety group, whereas there were virtually no such responders in the nonanxious ADHD group. There was no evidence that the ADHD with anxiety children suffered any unusual side effects, nor did they appear to get more anxious. Of course, 30% of the ADHD-anxiety children did respond well to stimulants and continued treatment with methylphenidate, thus the study did not show that stimulants are absolutely contradicted in children with ADHD with anxiety. In contrast, Tannock et al 97 did find that side effects of stimulants appear greater in the ADHD-anxiety group relative to the ADHD-alone grou p . Furthermore, the ADHD children were followed while they received long-term methylphenidate treatment (over 12 months). ADHD-anxiety children not only had less behavioral improvement but what improvement there was tended to decline over time.96 Dupaul et al3 6 divided ADHD children into internalizers and noninternalizers based on the child's baseline Child Behavior Checklist score. Similar to Pliszka, 85 they found that ADHD children with comorbid internalizing symptoms had a less robust response to stimulants than nonanxious ADHD children. Buitelaar et al27 also found low anxiety to predict a good stimulant response in an unselected group of ADHD children. More recent work, however, has not confirmed these findings. Diamond et al3 4 found that anxious and nonanxious ADHD children had equally robust responses to methylphenidate in a short-term trial. In the recently completed MTA study more than 100 children received a double-blind placebo-controlled crossover trial of methylphenidate; one third of the children had comorbid anxiety disorders. Anxiety did not predict nonresponse to stimulant medication. The MTA study also
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showed that anxious ADHD children were more likely to benefit from a combination of medication and psychosocial treatment than nonanxious ADHD children. 100 The nonanxious ADHD children did not derive added benefit from the combination treatment over that provided by medication alone. Recently, specific serotonin reuptake inhibitors have been successful in open trials in treating children and adolescents with anxiety disorders. 22• 39 These medications can be combined with stimulants, as noted in the following discussion of depressive comorbidity. ADHD AND DEPRESSIVE DISORDERS
As with anxiety, reliability of parent and child report is lower for depressive symptoms than ODD-CD symptoms.ss, 82• 90 What should the clinician do if the child and parent reports of depression differ? For instance, the child may report he or she is depressed, feels guilty, and has trouble sleeping but deny all other problems. The parent may deny the child is depressed, but report concentration difficulties and loss of appetite. Should the total symptoms from the parent and child interview be combined to yield a diagnosis of MDD? This is what is done in most clinical practices, yet each clinician has developed a different method of doing it. Other studies rely only on the parent report, but if a parent says the child is depressed whereas the child strenuously denies depression, are we making a valid diagnosis? If we use the child report, then we must examine the issue as to how children at different developmental levels express their symptoms. In the Diagnostic and Statistical Manual (Fourth Edition), "irritable mood" can be used in the place of depressed mood to make a diagnosis of affective disorder in children, but children with ODD and CD often are irritable as part of their temper outbursts. Even children with ADHD alone may be emotionally labile as part of their impulsiveness. Given these issues, it is not surprising that studies have yielded highly discrepant results as to the prevalence of affective disorder in the ADHD population, with estimates ranging from 3% (which is not greater than that in the general population) to as high as 75%. 18 ADHD children in community samples show lower rates of MDD than those in clinical samples, suggesting a role for referral bias. 1• 14• 19 The MTA study found that 6% of their sample met criteria for a depressive disorder. 100 No study has directly compared ADHD children with and without MDD on specific clinical measures. Depressive symptoms generally have an onset after the ADHD symptoms, 11• 64 and the co-existence of ADHD and MDD does not appear to prolong the depressive episode or number of depressive episodes. 64• 66 ADHD is not associated with an increased risk of suicide attempts or suicide completion, 24• 26 it is the comorbidity of CD or substance abuse that increases such a risk. 2s How do clinicians distinguish between MDD in an ADHD child and "demoralization"? It is not uncommon to encounter children with
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ADHD who are dysphoric about the consequences of their ADHD behavior. Such children may appear depressed, but the dysphoria is shortlived and occurs following a disciplinary event. When asked if he or she is depressed, the child may state that he or she is sad because he or she was grounded for not turning in a homework assignment. Energy loss, guilt for things that are not the child's fault, suicidal ideation, or other neurovegetative signs are absent. A child should only be diagnosed with MOD if the depressed mood is present nearly every day for several hours and there are prominent neurovegetative signs. When MOD is clearly diagnosed, it follows its own independent course, persisting (if untreated) even if the ADHD symptoms remit. 16 In contrast, "demoralization" will resolve when the ADHD symptoms are treated successfully. Thus, if depressive symptoms continue after the child has responded to medication treatment of the ADHD, further treatment of the depression should be pursued. Depressed ADHD children and adolescents also are more likely to show a negative cognitive style, often found in adults with MDD. 9• 16 Compared with ADHD children without depression, ADHD-MDD youth have more negative views of themselves and more "depressogenic" attributions; 9 that is, they tend to view positive outcomes as related to chance, rather than their efforts, and negative outcomes are always viewed as personal failures. Biederman et al1 4 examined the prevalence of both ADHD and MOD in families of ADHD children with and without MOD. If the child had ADHD alone, the rates of ADHD and MOD in first-degree relatives were both elevated over the rates of a control group. A similar pattern was found in relatives of the ADHD-MDD children. The fact that nondepressed ADHD probands also had an increased risk of MOD in their relatives suggested some common familial links with ADHD and MOD. It should noted that these studies primarily used parent reports to make the diagnosis of MOD, and many of the ADHD children in the study were not past the age of risk for MOD. If they developed MOD in the future, this would move them (and their depressed relatives) into the ADHD-MDD group and reduce the prevalence of MOD in the relatives of the ADHD-only group. No studies have compared stimulant responsiveness in ADHD and ADHD-MDD subgroups, nor have there been any studies of differential response of these groups to psychotherapy. It might be assumed that tricyclic antidepressants would be the first choice for medication treatment; numerous studies have shown, however, that tricyclic antidepressants are not effective in the treatment of childhood MD0. 83 Recently, paroxetine was found to be superior to placebo in the treatment of adolescent MOD, but imipramine was not. 57 Fluoxetine was also better than placebo in a controlled trial in children and adolescents. 38 Fluoxetine was combined with methylphenidate (20 mg/ day) to treat 32 ADHD children and adolescents with comorbid mood disorders and C0. 44 No unusual side effects were encountered in this open trial, although controlled trials are needed. If a child with ADHD and MOD responds to stimulants but remains depressed, adding fluoxetine
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(10-20 mg/ day), sertraline (50-200 mg/ day), or paroxetine (10-30 mg/ day) may be beneficial. More detailed dosing guidelines for these medications can be found elsewhere. 67 ADHD AND BIPOLAR DISORDER
How prevalent is BD in children with ADHD? This topic has generated heated controversy and has grown out of the more general issue as to the prevalence of BD in children and adolescents. Epidemiologic studiesI, 4 , 32 have not found high rates of the disorder. Early studies did show that children diagnosed as manic have a high prevalence of symptoms of ADHD and other externalizing disorders,29 and there is a high rate of mania among ADHD children in institutional settings.IOI Thus part of this debate is influenced by referral bias. A primary care physician seeing primarily outpatient ADHD might go an entire career without encountering a case of BD, whereas a psychiatrist in a hospital or tertiary care setting might see children who meet criteria for mania on a weekly basis. Wozniak et al1°6 examined 262 clinically referred prepubertal children and found 43 that met criteria for mania; all but one of these children also met criteria for ADHD. Within this sample there were 164 cases of non-BD ADHD, thus the rate of mania in this sample of ADHD children was 16%. There were only two children with euphoric mania; 77% showed "extreme and persistent mania." Eighty-four percent showed "mixed mania" in which mania and MDD symptoms co-occurred. Compared with non-BD ADHD children, the comorbid group showed a higher rate of RD and lower Global Assessment of Functioning scores. They also had higher rates of other psychiatric disorders, including conduct, anxiety, and depressive disorders. Similar results emerged from a second sample of ADHD children studied by this group.Is Child Behavior Checklist scores of manic ADHD children were elevated over those of nonmanic ADHD children on nearly all subscales, but particularly on the Aggression subscale. ADHD-manic children were found to have higher rates of BD among their relatives, whereas the rate of BD in the relatives of nonmanic ADHD children did not exceed that of a control group.Is, 107 After screening many referrals, Geller et al46• 47 identified 60 prepubertal children with mania. Nearly all of these children had ADHD as well. The manic children were compared with 60 matched controls who had ADHD but no mood disorder. Factors that Geller et al46' 47 found most differentiated ADHD-manic from ADHD nonmanic patients were as follows: grandiosity (85% versus 6.7%), elated mood (87% versus 5%), racing thoughts (48 versus 0%), and hypersexuality (45% versus 8%). The results obtained by Geller et al46, 47 were largely consistent with those of the Massachusetts General Hospital (MGH)Is, Io6 group, with the exception that the Geller et al46' 47 group in St. Louis found higher rates of elated mood whereas the MGH group found primarily irritable mood.
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Not all investigators accept the results of the MGH and St. Louis groups, however. This disagreement has been aired recently. 10• 6 ° Klein et al 60 criticize the MGH group for not requiring distinct cycles of manic symptoms. They state that the MGH findings are inconsistent with the low rate of BO found in epidemiologic samples as well as the follow-up studies of ADHD children that do not show any cases of B0. 50• 103 Biederman10 replied that childhood-onset BO may well present differently from adult BO and such early onset cases may have severe, persistent mania. Geller et al46• 47 have argued from their data that childhood manic patients may have "ultraradian" cycles: that is, they may move in and out of mania within several hours. Wilens et al1°5 also argued that epidemiologic and early follow-up studies may well have missed more severely disturbed children because they were excluded from the studies. While the debate continues, there is no doubt that there are a subset of severely disturbed children with ADHD: they have very irritable mood and dangerous aggression, and are only partially responsive to stimulants. Whether they have a formal diagnosis of BO or not, mood stabilizers may be of benefit. Lithium is superior to placebo in adolescent B0. 45 Lithium also has been found to be superior to placebo in reducing aggressive behavior in the inpatient setting. 28 A combined approach, using both lithium and stimulants, may be necessary in the ADHD-CD child to treat the full range of both inattentive and aggressive symptoms. With proper monitoring, these drugs can be combined safely. 30 Divalproex sodium, found to be effective in adult mania, 23 has shown promise in adolescent mania, although no controlled trials have been performed.78 Even in the absence of clear-cut mania, divalproex sodium has been shown to reduce aggressive outbursts both in open35 and controlled trials. 94 Stimulants can be combined with divalproex sodium without difficulty. The decision as to whether to start stimulants or a mood stabilizer first in the ADHD-manic child is complex. Pliszka et al 86 provide extensive guidelines on this matter. CONCLUSIONS
A rich body of data has emerged demonstrating the association of ADHD with other psychiatric disorders. ADHD with CD clearly appears to be a distinct subtype, and although it responds well to stimulants in the short run, the long-term course is quite stormy. Learning disorders are independent of ADHD, and their co-occurrence does not appear to influence the child's response to stimulants. Anxiety disorders also seem to be independent of ADHD. When ADHD children are anxious, they show lower impulsiveness, although they are still impaired on this dimension relative to controls. Their response to stimulants may be poorer than that of children with ADHD alone, although recent data challenge this view. They may, however, be more responsive to a combined approach of medication and psychosocial intervention. The pat-
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tern with mood disorders is much less clear, and further research is needed to examine the prevalence of BD among ADHD children. Advances in neuroimaging and genetics may lead to a greater understanding of the comorbidity of ADHD with other psychiatric disorders.
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Address reprint requests to Steven R. Pliszka, MD UTHSCSA, Department of Psychiatry 7703 Floyd Curl Drive San Antonio, TX 78229- 3900 e-mail: [email protected]