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ADHD and Comorbidity

  • Authors: Steffany J. Fredman, MA ; Martin L. Korn, MD
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Target Audience and Goal Statement

This activity is intended for physicians, pharmacists and registered nurses.

The goal of this activity is to provide current treatment protocols and clinical strategies for the treatment and management of psychiatric disorders and to update the clinician and the researcher on the latest developments in psychiatry and mental health.

On completion of this continuing medical education offering, participants will be able to:

  1. Recognize the symptoms and issues of comorbidity of ADHD

  2. Review the pharmacological treatment of ADHD

  3. Evaluate the clinical features and genetic issues in eating disorders


  • Steffany J. Fredman, MA

    Doctoral candidate, Department of Clinical Psychology, University of North Carolina at Chapel Hill

  • Martin L. Korn, MD

    Psychiatrist, Department of Psychiatry, The Mount Vernon Hospital, Mount Vernon, New York

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ADHD and Comorbidity

Authors: Steffany J. Fredman, MA ; Martin L. Korn, MDFaculty and Disclosures



Attention Deficit Hyperactivity Disorder (ADHD) affects 3% to 6% of school age children. The risk for comorbidity with other psychiatric disorders is high,[1] and the presence of comorbid disorders warrants special consideration in the treatment of patients with this disorder. Speakers at the 154th Annual Meeting of the American Psychiatric Association in New Orleans, Louisiana, addressed diagnostic and treatment implications for ADHD in the context of other Axis I disorders.


Overview of Comorbid Conditions in ADHD

In an review of the clinical presentation of this disorder, Joseph Biederman, MD,[2] of the Massachusetts General Hospital, Boston, noted that the psychiatric disorder currently known as "ADHD" has evolved considerably over time. Initial conceptualization of the disorder from the 1930s to the 1960s emphasized the potential for minimal brain damage or dysfunction. With the advent of the Diagnostic and Statistical Manual of Mental Disorders, Second Edition (DSM-II) in 1968, the syndrome was entitled "hyperkinetic reaction of childhood," stressing the motor aspects . As the understanding of the disorder evolved in the 1980s, both attentional and impulsive/hyperactivity components were stressed. Current DSM-IV nomenclature of ADHD reflects this change. Three subtypes of the syndrome have been delineated in the DSM-IV, including ADHD predominantly inattentive, ADHD predominantly hyperactive-impulsive, and ADHD combined type. The ADHD combined type is the most common and the inattentive type is rare. Numerous studies have confirmed that the disorder is prevalent worldwide as school-age children in all countries suffer from this disorder.[1]


Etiological Considerations

The etiologic contributions to ADHD are complex and include neuroanatomic abnormalities, neurobiologic dysregulation, CNS insults, genetics, and environmental factors. Neurobiologic abnormalities in the prefrontal cortex and anterior cingulate have been demonstrated in ADHD. The prefrontal cortex is involved in executive functioning while the cingulate gyrus is involved in focusing attention and mediating response selection. Among individuals with ADHD, consistent findings have emerged regarding decreased dopaminergic transmission in these areas. The dopamine 4 (D4) receptor, which is related to cognitive and emotional functioning, is densely located in the prefrontal cortex of the brain. Genetic studies indicate that the DRD4-7 repeat allele occurs at a higher rate among children with ADHD than among controls. This gene has been associated with the psychological personality dimension of "novelty seeking" and may account for some portion of the genetic contributions to ADHD.[3,4]

In addition to genetic contributions to the development of ADHD, there are also numerous environmental factors that may predispose individuals to ADHD. The risk of developing ADHD is increased 2-fold by either maternal smoking or alcohol abuse. Low birth rate, which may have both genetic and environmental causes, is also associated with ADHD.[5]


Clinical Presentations

Although ADHD has historically been identified primarily in boys, a substantial number of girls suffer from ADHD as well. Among clinic referred samples, the male/female ratio of ADHD is 9-10/1. However, community samples, which are generally believed to more accurately represent the population prevalence, have found an approximately 2-3/1 male/female ratio. The substantially higher rate in referred samples is probably due to the higher prevalence of behavioral and conduct problems in boys leading to an increased referral rate and thus resulting in research biased toward males. In a comparative of study of boys and girls with ADHD,[6] both sexes were comparable in terms of rates of inattention, impulsivity, hyperactivity, and comorbidity. However, rates of conduct disorder were approximately 20% in boys and 8% girls. Oppositional defiant disorder was manifested in approximately 62% of boys compared with 32% of girls.


Comorbidity in ADHD

Stephen Faraone, PhD,[7] of Harvard Medical School, Boston, Massachusetts, reviewed the patterns of comorbidity in ADHD. Because ADHD is highly comorbid with other psychiatric disorders, there has been controversy as to whether it exists as a primary disorder or only secondary to other psychiatric syndromes. The nosological system advocated in the DSM is a hierarchical one. That is, in the presence of 2 or more diagnoses, 1 should be considered primary and account for many of the symptoms observed in the secondary syndrome. There is mounting evidence, however, that many conditions exist concurrently with ADHD, and each modify the overall clinical presentation and treatment response. These comorbid conditions should be considered simultaneously in order to broaden our understanding and maximize treatment.

Depressed patients demonstrate diminished concentration and individuals with bipolar disorder often manifest psychomotor agitation and distractibility. It may be difficult to differentiate these symptoms from the cardinal symptoms of ADHD. There are several ways, however, to deal with symptom overlap in research and clinical settings. The "subtraction method" requires the same absolute number of symptoms to be present to diagnose either disorder, except that shared symptoms are "subtracted" or removed from diagnostic consideration. For example, 8 of 14 (57%) symptoms are needed for the diagnosis of ADHD in the DSM IV. If 2 overlap, symptoms are present between the 2 disorders, then 8 of 12 (67%) symptoms would be required to make the diagnosis with the subtraction method. Alternatively, in the "proportional" method the same ratio of symptoms would be required (ie, 7 of 12 [58%]). Milberger and colleagues[8] found that most patients with comorbid depression and ADHD still retained the diagnosis of ADHD whether the subtraction or proportional method was used. Long-term follow-up studies have demonstrated that individuals with ADHD and comorbid disorders have poorer prognoses and greater hospitalization rates than those with ADHD alone. There is often a persistence of ADHD and/or the comorbid condition for the duration of the several year follow-up period.[9]

Pharmacologic "dissection" studies have been conducted to determine clinical contributions of each of the comorbid disorders and treatment strategies. For example, an individual with comorbid ADHD and bipolar disorder may first be treated with stimulants. Usually, little change occurs with this treatment intervention. Alternatively, if a mood stabilizer is initiated first, significant improvement may be expected. If symptoms of ADHD continue to persist after mood stabilization, this gives support for the diagnosis of 2 co-occurring diagnoses. The addition of a stimulant may then be indicated. Therefore, unless both comorbid conditions are adequately treated, the ADHD symptoms may not remit. Pharmacologic studies of bipolar disorder and ADHD suggest that the 2 disorders exist as discrete entities in many patients.[10]


ADHD and Depressive Disorders

The overlap between depression and ADHD is now well recognized. Thomas Spencer, MD,[11] from Massachusetts General Hospital, elaborated on the relationship between ADHD and mood disorders. Children and adults referred for ADHD demonstrate a higher than chance incidence of depression, and individuals referred for depression show elevated rates of ADHD. Given that the presence of an underlying or co-occurring mood disorder may complicate the treatment of ADHD, sufficient attention to and proper treatment of the mood disorder is imperative.

Historically, juvenile depression was not thought to exist, but recent evidence indicates that the disorder is manifested in childhood, but may be manifested in various ways. Depressed children tend to present with irritability, negativism, social withdrawal, school dysfunction, and somatic disorders. Since these symptoms may be attributed to normal childhood behaviors, the diagnosis may be missed. The average age of children referred to the Massachusetts General Hospital for depression is 11 years with a mean duration of depression of 3 years.

There is a high rate of comorbidity between ADHD and depression. In a long-term follow-up study (N = 237) by Biederman and colleagues,[12] the baseline rate of major depression in children diagnosed with ADHD was approximately 30%. At 4 years, the rate was over 40% in children with ADHD compared with approximately 5% in controls. The children with comorbid disorders manifested high rates of a variety of disorders including bipolar disorder and anxiety disorder. The comorbid group was more dysfunctional and had higher hospitalization rates as well as lower global functioning scores compared with children diagnosed with pure ADHD.

Examination of the data using depression as the index diagnosis reveals similar findings. In the Biederman study,[13] 70% of children referred for either severe or mild depression were found to have comorbid ADHD. Moreover, the younger the age of onset of depression, the higher the prevalence of ADHD in the children. When classified by age, rates of ADHD were 84% in children ages 0 to 7 years, 66% in children ages 8 to 12 years, and 39% in children ages 13 to 18 years. Data from other investigators are consistent with these high comorbid rates. Butler and colleagues[14] observed that among hospitalized children with ADHD (N = 76), 36% had depression, 22% had bipolar disorder, 3% had dysthymia, and 8% had an affective psychosis. Only 31% had no concurrent affective diagnosis.

Family studies suggest that there is some genetic link between depression and ADHD. Biederman and colleagues[15] found that the rates of ADHD among the relatives of children with ADHD with or without depression were significantly higher than among relatives of control children. This suggests that for some children, the same gene may contribute to ADHD, whereas in others it could contribute to depression or the co-occurrence of both disorders.

With regard to treatment, most treatments that are effective for ADHD (ie, stimulants) do not significantly improve depression. In addition, treatments for mood disorders are generally not helpful for ADHD. Furthermore, in the presence of a comorbid mood disorder, the stimulants themselves are less effective for ADHD. Nonstimulant treatments that are noradrenergic but not serotonergic, are effective for ADHD. In contrast, serotonergic antidepressants are effective for juvenile depression but not for ADHD.[16,17]

Buproprion, an agent that affects both noradrenergic and dopaminergic neurotransmission, has been shown to be efficacious for adolescents with comorbid ADHD and depression. In an open-label study,[18] bupropion SR was effective for both disorders in 58% of the adolescents treated (N = 24). Interestingly, in this study, improvement of ADHD appeared tied to improvement in depression. That is, if the patient's depression responded, there was a 58% ADHD response rate and a 29% nonresponse rate. If the depression did not respond, the ADHD response rate was only 4%. Thus, as in other disorders comorbid with ADHD, to maximize the response rate, it is important that both disorders be treated simultaneously. Findings of studies using the combination of stimulants and SSRIs for comorbid ADHD and depression are consistent with this observation.[19,20]


ADHD and Bipolar Disorder

There are many challenging issues in the treatment of children with comorbid bipolar disorder and ADHD according to Janet Wozniak, MD,[21] The rate of bipolar disorder in children has been underestimated. As with depression, the presentation of the disorder in children is different than in adults and may be difficult to distinguish from normal developmental issues. Manic children tend to demonstrate irritability, anger, and oppositional or aggressive behavior rather than euphoria. Symptoms such as grandiosity, racing thoughts, and pressured speech are often present, however. Manic outbursts in children may be intense but be relatively short-lived and have been termed "affective storms" for these reasons .[22]

Because of symptoms shared between mania and ADHD, it may be difficult to discern whether the child has bipolar disorder, ADHD, or both. Specifically, mania and ADHD in children overlap with respect to distractibility, physical hyperactivity, and talkativeness. Because children with noncomorbid ADHD do not manifest mood disturbances, the presence of mood instability suggests the presence of bipolar syndrome.

Fifty percent of prepubescent depressed children in one sample manifested symptoms of bipolar disorder within 10 years of the onset of depression.[23] Another study found that 20% of depressed adolescents in another sample had revealed a bipolar disorder within 1-4 years.[24] In a study of children referred for a psychopharmacologic evaluation, 16% of the children under 12 met the criteria for mania.[25] All but 1 of the children meeting criteria for mania also met criteria for ADHD. When comparing the children with ADHD without mania, the manic children had significantly higher rates of major depression, psychosis, multiple anxiety disorders, conduct disorder, and oppositional defiant disorder as well as significantly greater impairment in psychosocial functioning.[25]

As with depression, bipolar disorder must be treated effectively for the symptoms of ADHD to resolve in the comorbidly afflicted individual. Atypical antipsychotic agents appear to be effective in the amelioration of juvenile mania. In an open-label study,[26] resperidone was found to be an effective antimanic agent, but did not help ADHD symptoms. Among bipolar adults comorbid for ADHD, bupropion is effective for ADHD and depression, and may have a lower potential for inducing mania. Wilens and colleagues[27] demonstrated that sustained release bupropion 200 mg twice daily significantly decreased symptoms on the DSM-IV ADHD Symptom Checklist by 52%. In addition, significant improvements in mania and depression were observed.


ADHD and Substance Abuse

ADHD, with or without comorbidity, is a risk factor for the occurrence of substance abuse among adults.[28,29] Timothy Wilens, MD,[30] from Massachusetts General Hospital, reviewed the risk factors associated with these comorbid conditions. When an individual presents with both substance abuse and ADHD, clinicians should first attempt to stabilize and treat the substance abuse disorder. Depression should subsequently be treated followed lastly by treatment of the ADHD.

Buproprion and tricyclics are typically considered first-line pharmacotherapy for comorbid ADHD and substance abuse disorders in children and adolescents. Second-line agents are the stimulants, and these medications are generally thought to be safe and efficacious for the treatment of ADHD among substance-abusing individuals. Substance-abusing patients treated with methylphenidate demonstrated a reduction in ADHD symptoms as well as an improvement in cocaine craving in some studies[31] or no increase in craving in other studies.[32] Care should be exercised, though, when choosing individual stimulants among substance abusing populations. For instance, pemoline is associated with low abuse liability, whereas methamphetamine should be avoided because of its high potential for abuse. The use of agents with intermediate abuse potential may be ameliorated by using extended-release preparations of methylphenidate or amphetamine.

A common concern is that the treatment of children with stimulants will increase the rates of substance abuse over the long term. However, findings from retrospective and prospective studies do not support this hypothesis, particularly when controlling for baseline severity. In fact, successful treatment of ADHD in childhood or adolescence appears to have protective effects with respect to the development of later substance abuse. In a 4-year follow-up study of ADHD and non-ADHD families, Biederman and colleagues[33] observed the patients with untreated ADHD had much higher rates of later substance abuse compared with both treated ADHD patients and controls. Untreated ADHD is also associated with higher rates of alcohol use at 15-year follow-up.[34] Thus, although ADHD and substance abuse are highly comorbid among adults, treatment of ADHD in children or adolescents may actually offer protection against later substance abuse.



The syndrome of ADHD is frequently associated with coexisting psychiatric disorders, and this comorbidity does not appear to represent an artifact of assessment. In the assessment as well as treatment process, it is important to diagnosis and treat all comorbidities in order to maximize treatment. Since comorbid conditions are associated with greater cognitive, social, and psychological impairments, early vigorous intervention is warranted.



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