Anthony L. Rostain, MD, MA

 in 1980, attention-deficit/ hyperactivity disorder (ADHD) has proved to be a developmental disorder with many causes and complex behavioral, cognitive, and emotional manifestations that can impair academic functioning, occupational achievement, social relationships, and self-esteem.

 The immediate and long-term impairments of ADHD are of great concern, particularly as more and more longitudinal studies document lifelong patterns of underachievement, sexual-reproductive and driving risks, alcohol and substance abuse, mood disorders, and reduced executive functions and coping skills.

Recently, comorbid psychiatric conditions associated with ADHD have been identified as major obstacles to successful treatment and functional outcomes. The high prevalence of these conditions (

) along with their negative impact on treatment outcomes has been documented in numerous studies of patients across their life spans.

 It is evident that comorbid conditions impose heavier burdens on patients with ADHD (as well as their families), and that they make it more difficult for clinicians to choose interventions that are likely to succeed with a high degree of certainty. Whereas the evidence base for multimodal treatment of ADHD "simplex" in children and adolescents is well established,

 such is not the case for patients with complex forms of the disorder.

The following case vignette illustrates a common occurrence in modern psychiatric practice: the presence of severe comorbidity in ADHD patients leading to a less than optimal treatment outcome.

Tommy is a 13-year-old boy with severe combined-type ADHD and dyslexia who is in your office with his family for a follow-up visit to discuss how his stimulant medication is working.	

His parents report that his teachers see a modest improvement in his ability to focus in class and get his class work done, along with less calling out, tapping on the table, and fidgeting in his seat.	

By contrast, at home, Tommy is very argumentative about doing his homework and has refused to do it altogether. He is easily angered, has been having difficulty with  sleeping, and has been spending less time with friends and family members, preferring to stay in his bedroom playing computer games.

In your office, Tommy confides that he is worried about his ability to handle all the demands of his seventh-grade teachers, many of whom he dislikes. He expresses a great deal of negativity about school and feels convinced that he is "too stupid to make it." Tommy requests that he no longer be required to take medication because he thinks it is not helping him and instead makes him feel "weird and dull."

This article reviews the causes of treatment resistance in young patients with ADHD and describes strategies for integrating pharmacotherapy and psychotherapy to avoid resistance and promote optimal functioning.

The NIMH Multimodal Treatment Study of Children With Attention-Deficit/ Hyperactivity Disorder (MTA study) is the largest and most comprehensive study of the differential effects of 4 treatment strategies after 14 months of intervention on the core symptoms as well as key functional measures of childhood ADHD. The sample of 579 patients (80% males) enrolled in the study included 34% with comorbid anxiety disorder, 40% with oppositional defiant disorder, 14% with conduct disorder, and 11% with a tic disorder. The socioeconomic status (SES) of the study sample was 19% low income, 41% lower-middle income, and 37% upper-middle income. Roughly 30% were living in single parent families, over 90% had parents who graduated from high school, and 84% of fathers and 72% of mothers were employed.

In addition to comparing the efficacy of different treatment strategies (stimulant medication treatment, behavior management, combined treatment, and community care), a major goal of the MTA study was to identify moderators (factors intrinsic to the sample) and mediators (factors pertaining to the intervention process) of treatment outcome.

 reviewed the extensive data collected from the study and found significant differences in treatment response based on the presence of several moderators (

). For example, chil-dren with comorbid anxiety disorders showed a stronger response to behavioral intervention (based on parental reports of ADHD and internalizing symptoms) than those without anxiety. Children from low SES families had a better response to combined treatment on teachers' ratings of social skills. Children with more severe initial ADHD symptoms showed a relatively poorer response to both medication management and combined treatment compared with those with less severe symptoms.

Children of parents who reported even mild depressive symptoms showed relatively poorer responses to these treatments, and those with intelligence quotient (IQ) scores of less than 100 who had severe ADHD symptoms also responded less favorably to these interventions. Quite surprisingly, the sex of the child, his or her previous experience with stimulant medication, and the presence of either oppositional defiant disorder or conduct disorder had no discernable impact on treatment response.

With respect to mediator variables, keeping appointments turned out to be a highly significant factor for patients in the medication-management group but not for patients in the behavior-treatment group. Children in the community care group who received medications fared better than those in the community group who were not taking medications, but the children in the community care group were not as improved as the children in the medical center-based medication or combined-treatment groups. Children in the combined-treatment group who showed the greatest improvement in classroom social skills and behavior were from families who displayed the most improvement in discipline methods.

 found that only 62% of the patients in the best outcome groups (medication management or combined treatment) had an excellent response (defined as reaching normal or near-normal status) compared with 30% of those who received behavior management or community care. In other words, even in the groups with the most favorable outcomes, more than one third of patients did not achieve an excellent response. This sobering fact is important to keep in mind when considering the prognosis for those who have ADHD.

Among children in the optimal treatment groups, having parents with even mild depression dropped the excellent response rate down to 45%. The investigators identified 5 moderator-defined groups of children receiving either combined or medication-management treatment:

Group A (low initial ADHD severity, low parental depression) had 73% excellent responders.

Group B (low initial ADHD severity, high parental depression) had 59% excellent responders.

Group C (high initial ADHD severity and high IQ, high parental depression) had 48% excellent responders.

Group D (high initial ADHD severity, low parental depression) had 48% excellent responders.

Group E (high initial ADHD severity and low IQ, high parental depression) had 10% excellent responders.

The clinical implications are clear: parental depression needs to be addressed when it is present, and when ADHD symptoms are severe, additional treatment approaches (as yet unidentified in published studies) may need to be used in order to maximize the chances for success.

Goals and methods for treating ADHD: current evidence

The results of the MTA study raise 2 important questions for clinicians when developing treatment plans for patients with ADHD and comorbidity:

Is the goal of intervention symptom improvement or remission?

How can treatment be designed to have maximal effects on the child or adolescent's functioning?

In their meta-analysis, Steele and colleagues

 proposed that remission be defined as "minimal or no symptoms of ADHD" (using standard rating scales). This would imply that on ADHD-rating measures, the average rating after treatment would be no more than 1 on scales that range from 0 to 3, and a score of no more than 2 on the Clinical Global Impressions Severity scale. The significance of achieving symptom remission is that it is associated with greater improvements in functional outcomes such as academic functioning,

The MTA study showed that methylphenidate alone, when titrated to optimal dosages, resulted in a 58% remission rate; when it was given in conjunction with behavior management, 68% of patients achieved remission. Only 34% of children who had received intensive behavior therapy alone (including parent training, summer camp, and classroom aides) achieved symptom remission.

Recently, randomized controlled clin- ical trials of ADHD medications have shown similar outcomes. In a study of 32 patients who received incremental daily doses of OROS methylphenidate (18, 36, and 54 mg), 66% achieved remission at the highest dosage.

 In a randomized open-label study of 143 patients, 44% achieved remission on OROS methylphenidate (average daily dose, 37.8 mg) versus 16% on immediate-release methylphenidate (average daily dose, 32.2 mg).

 The lower remis- sion rate for OROS methylphenidate may reflect the fact that lower dosages were administered. In a long-term (6-month) open-label trial of mixed amphetamine salts with 138 adolescent patients, remission rates averaged 61% with a range of 52% to 71% depending on the daily dosage given (10 to 40 mg).

 Two randomized controlled trials of atomoxetine reported remission rates of 28.6% and 27.0%, respectively, indicating a less robust response with this medication than with methylphen- idate and amphetamine.

Considering that ADHD has significant effects on cognitive, emotional, and behavioral domains of functioning, it is not surprising that medication treatment alone frequently does not induce remission, especially in patients with comorbidities. It is important to introduce psychosocial interventions in addition to pharmacotherapy to maximize outcomes. According to the American Academy of Child and Adolescent Psychiatry ADHD practice parameters,  parent training in child behavior management techniques, family-oriented cognitive-behavioral therapy, social skills training, and school-based interventions are essential ingredients of a comprehensive multimodal treatment plan.

 Moreover, the parameters state that comorbid conditions must also be treated (

 published a comprehensive review of the evidence for psychosocial treatments of ADHD. A number of these studies show that manualized parent training resulted in reductions in parenting stress and improvements in child social behavior and acceptance. Behaviorally based classroom interventions (such as daily report cards and contingency management programs) were also shown to improve classroom deportment and academic performance.

Academic interventions, such as task and instructional modification, homework assistance, peer tutoring, computer-assisted instruction, and strategy training, seem to benefit children with ADHD; however, there is a paucity of studies from which to derive valid estimates of treatment effect sizes. Large behavioral effects on both core symptoms and functional measures (eg, following rules, sports skills, self-esteem) have been demonstrated by summer treatment programs such as those that were incorporated in the MTA study. Also, social skills training interventions, while less studied than other approaches, have shown promise, especially when combined with parent training.	

With respect to interventions for adolescents with ADHD, far less is known than with children because there is nothing comparable to the MTA study. The absence of well-controlled studies combining medication and psychosocial treatment of adolescents with ADHD underscores the desperate need for more extensive research with this age group, especially in view of the serious health risks (eg, driving, sexual activity, substance abuse) faced by teenagers in the United States.

A study comparing behavior management training, problem solving, communication training, and structural family therapy found comparable improvements in various functional measures (eg, parent-child communication and conflict resolution, internalizing and externalizing symptoms, parent- reported school adjustment).

 A later study of the first 2 interventions (alone and in combination) found similar results.

 Group-based training for parents of adolescents with ADHD has also shown some promising results.

A literature review of academic interventions

 reported that school-based interventions appear to have moderate to large effects on specific behavioral targets (eg, reduced off-task behaviors, classroom disturbance) and academic performance, but only minimal gains have been seen in social functioning. As Weiss and colleagues

 have observed, there is dire need for more efficacy studies of outcomes in ADHD that can "tell us how our treatments meet the patient's expectation to be able to achieve a particular functional target."

Clinical approach to managing treatment-resistant ADHD

With the foregoing discussion in mind, it is important to approach each patient in a systematic and comprehensive fashion and to reassess the patient's diagnosis. Comorbid conditions such as learning disorders, anxiety and mood disorders, and executive dysfunction (including deficient working memory, organizational skills, and time perception) can reduce treatment efficacy. These require careful consideration by the clinician and will probably necessitate a revision of treatment goals and approaches. Patient and family educational sessions are useful for clarifying new information about the patient's condition, and for placing these findings in a broader context. For instance, the presence of learning disabilities might shift the focus of treatment to school-based interventions. Likewise, the appearance of anxiety or mood disorders, in either the child or the parents, might indicate the need to focus more on intensive family therapy approaches.

Medication nonadherence is a major source of treatment resistance and should be addressed in a nonjudgmental and balanced fashion. If nonadherence is because of ambivalence on the part of the patient and his parents, it is worthwhile to conduct motivational enhancement interviews to determine whether they are ready to accept responsibility for undertaking a medication regimen. It is valuable to find out the precise reasons why the patient and family are not willing to comply with treatment, and to learn about their views of the consequences (both positive and negative) of taking or not taking the prescribed medication.

The primary reason for nonadherence is often the appearance of adverse effects, especially in the face of equivocal clinical results. If this is so, it is vital that the clinician make adjustments to improve the cost-benefit ratio of treatment. This may be achieved by increasing the current dose of medication (to achieve greater symptom control), switching to a different class of medication, combining the current medication with another agent, or stopping medications altogether. More frequent visits to enable closer monitoring of pharmacotherapy may also promote greater adherence.

If initial treatment with a stimulant medication has not been successful, the Texas Children's Medication Algorithm for ADHD (

 introduced in 1998 and revised in 2004, recommends starting treatment with either methylphenidate or amphetamine and increasing the dosage to optimal levels as needed. If partial or nonresponse to medication results, a switch to another stimulant medication is advised. If this does not work, atomoxetine is used in place of a stimulant. If the response is not satisfactory, combining atomoxetine with a stimulant is recommended. Following this, bupropion or a tricyclic antidepressant is substituted for atomoxetine. As a last step, the addition of an a-agonist (guanfacine or clonidine) is advised. If there is still no satisfactory clinical response, a consultation with a specialist in ADHD pharmacology may be in order.

Other medication combinations have been beneficial for some patients. For instance, the combination of an SSRI and a stimulant can be quite effective for patients with ADHD and comorbid anxiety disorders, including generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. Atomoxetine is also useful for ADHD patients with these conditions.

 Patients who experience adverse effects with stimulants seem to tolerate modafinil quite well, although the absence of FDA approval for ADHD has created an economic barrier for many families who cannot afford to pay out-of-pocket for this medication. Venlafaxine appears to be helpful in adolescents and adults with ADHD and comorbid anxiety and/or depression. With cautious dosing, stimulant medication can be safely added to venlafaxine, although careful cardiovascular monitoring is recommended. Finally, small open-label studies and case series have shown a modest benefit with monoamine oxidase inhibitors, the an- ticholinesterase inhibitor donepezil, and the combination of stimulant and a-agonist.

Turning to the issue of inadequate response to psychosocial interventions, one of the most important findings from the MTA study is the strongly negative impact that parental depression has on treatment outcomes. Considering this, along with the fact that many parents of ADHD children have ADHD themselves, it is important that the astute clinician pay attention to how parents are faring. If there is evidence of excess stress or burnout (as evidenced by direct and indirect statements, nonverbal cues, or inconsistent attendance at office visits), it makes sense to schedule a separate session to discuss the parents' issues. Severe parental psychopathology (eg, substance abuse, major mood disorders, psychosis) can be especially difficult to address and might require enlisting other family members to help the individual obtain treatment.

Above all else, it is vital that the clinician maintain respect for the significance of the parent's role in the life of his or her child or adolescent. The vulnerabilities, needs, resources, and capacities of each parent must be taken into consideration whenever a psychosocial intervention is attempted. The demands of family-oriented treatment (eg, completing homework assignments between sessions, changing one's habitual responses to the child's negative behavior, making time, and paying for sessions) should not be overlooked and, when appropriate, genuine appreciation for the parent's dedication and involvement in the process of helping the child who has ADHD should be generously provided.

Attempts must be made to work with the child's educational setting, especially if there are serious conflicts between family members and the school staff. Even the best efforts to assist patient and family cope with ADHD are neutralized by intransigent or antagonistic school personnel, especially the child's teachers. It is especially important to talk directly with school staff to reduce misunderstandings and promote a collaborative approach to help the child succeed in school. When an individualized education program or a Section 504 plan is not being effectively implemented, it is helpful to alert the school, and to offer to meet in person to discuss ways to put needed accommodations into place. As much as possible, the clinician should act as an advocate for the child while maintaining a pragmatic appraisal of the resources of the school and the school district. Unrealistic expectations on the part of the child or family about the capacity of the school to meet every aspect of the child's academic and social needs should be gently but firmly confronted and educational options (including approved private schools or home schooling) should be discussed if family-school conflicts appear insurmountable.

Tommy's presentation at the office visit suggested that his anxiety about school was extremely high and that he had a depressed mood. Further exploration revealed that he truly felt worse when he was taking the medication, and that his ability and motivation to complete his homework assignments were virtually nonexistent. His medication was switched to atomoxetine, which resulted in moderate improvement in concentration and a marked reduction in anxiety symptoms.

A telephone call to the school led to an immediate reduction in homework and an increase in resource-room time to make up for missing assignments. The school guidance counselor made time to speak to Tommy on a regular basis about his negative views toward school, and over the ensuing month, his attitude began to shift in a more positive direction.

Family therapy sessions were geared toward changing unrealistic parental expectations and anxiety about academics and de-escalating their preoccupations with Tommy's homework in favor of developing more positive interactions  with him. During the next few months, Tommy started taking more responsibility for homework and began spending more time socializing with family and friends.

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Articles

Since its introduction in DSM-III in 1980, attention-deficit/ hyperactivity disorder (ADHD) has proved to be a developmental disorder with many causes and complex behavioral, cognitive, and emotional manifestations that can impair academic functioning, occupational achievement, social relationships, and self-esteem.

Anthony L. Rostain, MD, MA

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Treatment Resistance in Youths With ADHD and Comorbid Conditions