Expert Roundtable Supplement 

   

Funding for this expert roundtable supplement has been provided by an educational grant from Eli Lilly and Company.

 

This supplement to Primary Psychiatry as well as additional enduring materials and archived issues are available at www.primarypsychiatry.com.

 

Accreditation Statement
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 


Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at The Mount Sinai School of Medicine.

Statement of Need and Purpose
Although attention-deficit/hyperactivity disorder (ADHD) is often considered a childhood disease, up to two-thirds of all children with ADHD continue to show symptoms in adulthood. Adults with ADHD experience decreased productivity and underachievement in the form of chronic lateness, poor management of time and money, inattention to detail, and forgetfulness. There are no psychological evaluations or laboratory tests that can confirm an ADHD diagnosis, and doctors familiar with childhood ADHD often have difficulty detecting adult ADHD due to its changed presentation. Diagnosis is further complicated by the many comorbidies associated with ADHD. Eighty-seven percent of adult ADHD patients exhibit at least one comorbid condition. Anxiety disorders, depressive disorders, and substance use disorders are common among adults with ADHD. Due to different presentation, comorbidities, and the need to establish long-term, continuous symptoms, many primary care physicians are hesitant to diagnose and treat adult ADHD.

Medications proven effective in treating childhood ADHD are also successful in treating adult ADHD. The most commonly prescribed medications are stimulants, such as methlyphenidate, amphetamines, and dextroamphetamines. Stimulants and atomoxetine, a relatively new nonstimulant medication, are generally considered the best options for initial pharmacologic treatment. Psychosocial treatment, in conjunction with pharmacologic treatment or alone in patients with mild ADHD, is highly effective at controlling adult ADHD symptoms.

Target Audience
This activity is designed to meet the educational needs of primary care physicians and psychiatrists.

Goal of the Activity
• To educate physicians on issues of diagnosis and therapeutic options in adults with attention-deficit/hyperactivy disorder, with consideration of the complications of comorbidity in this population and medication management strategies (eg, dosage) that differ in adults compared to children and adolescents.


Learning Objectives

• Assess adult patients for attention-deficit/hyperactivity disorder (ADHD) through differential diagnosis and consideration for psychiatric comorbidities.
• Recognize appropriate management strategies according to patient comorbidities and symptomatology subtypes.
• Explain the safety, efficacy, and mechanism of action of ADHD medications for patients, considering dosage differences for the adult population.

Faculty Affiliations and Disclosures

Jeffrey H. Newcorn, MD, is a consultant/advisor to and receives honoraria from Cortex, Eli Lilly, Lupin, McNeil, Novartis, Pfizer, and Shire.

Mark A. Stein, PhD, receives research support from Cephalon, Eli Lilly, McNeil, and Novartis; and receives honoraria and compensation for service on the advisory boards of Cortex, McNeil, Novartis, Pfizer, and Shire.

Margaret Weiss, MD, PhD, is a consultant and/or advisor to, and has received or receives honoraria, consulting fees, or research support from Cephalon, Circa Dia, Eli Lilly, Janssen, Novartis, Purdue, and Shire.

Acknowledgment of Commercial Support
Funding for this activity has been provided by an educational grant from Eli Lilly and Company.

Peer Reviewers
David L. Ginsberg, MD, receives honoraria and research
support from AstraZeneca, Cyberonics, and GlaxoSmithKline.
Eric Hollander, MD, reports no financial, academic, or other support that may pose a conflict of interest.

To Receive Credit for this Activity
Read this supplement, reflect on the information presented, and complete the CME quiz. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged to measure outcomes for this CME activity. Please submit this posttest by August 1, 2009 to be eligible for credit.

Release date: August 1, 2007
Termination date: August 31, 2009

The estimated time to complete this activity is 1 hour.

Abstract

 

Attention-deficit/hyperactivity disorder (ADHD) is an impairing but usually treatable condition. Popular culture propagates the myth that ADHD recedes with age; this is not the case. Although it is common, <20% of adults with ADHD are diagnosed or treated. Adults with ADHD show significant comorbidities with depressive disorders, anxiety disorders, substance use, oppositional defiant disorder, personality disorders, sleep problems, and learning disabilities. However, symptoms that result from ADHD, such as mood symptoms or lability, are often mistaken for comorbid disorders. Comorbidity with ADHD impacts treatment compliance, treatment response, and patient insight. Insufficient data on the interaction between ADHD and comorbidities impedes proper diagnosis and treatment. Better clinical tools for assessing these conditions are needed. Food and Drug Administration-approved pharmacologic treatments for adult ADHD include stimulants, dexmethylphenidate, and the nonstimulant atomoxetine. Effect sizes of approved medicines at approved doses are half those seen in children. Adults may also need longer duration of medication effects than children. Short-acting stimulants are likely to result in poorer adherence and have a higher risk for diversion or abuse. Risk of abuse is a major concern; stimulant treatments are controlled substances, and children with ADHD show increased risk of substance abuse. Psychosocial interventions may be beneficial in treating both ADHD and comorbidities.


In this expert roundtable supplement, Margaret Weiss, MD, PhD, presents a comprehensive overview of complications surrounding differential diagnosis in adults with ADHD. Next, Mark A. Stein, PhD, reviews evaluation, comorbidity, and development of a treatment plan in this population. Finally, Jeffrey H. Newcorn, MD, provides a discussion on the pharmacologic options available for adults with ADHD, considering dosages specific to adults and common comorbidities.

 

 

 

Differential Diagnosis and Comorbidity in Adults with ADHD

 

By Margaret Weiss, MD, PhD

 

 

 

Dr. Weiss is director of research for the Division of Child Psychiatry, University of British Columbia, and senior scientist for the Child and Family Research Institute in Vancouver, British Columbia.

 

Disclosures: Dr. Weiss is a consultant and/or advisor to, and has received or receives honoraria, consulting fees, or research support from Cephalon, Circa Dia, Eli Lilly, Janssen, Novartis, Purdue, and Shire.

 

Acknowledgment: The author would like to thank Dr. Gabrielle Weiss for her contributions to this article.

 

  

 

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common, impairing, and treatable condition. Recognition and treatment of ADHD affords an impressive opportunity for treatment. While there is a large demand for service, few settings are able to structure service sufficient to meet this need, and <20% of adults with ADHD have been diagnosed or treated.1 The rate-limiting step in translating recent advances in therapeutics for management of ADHD into clinical practice is a shortage of adequately trained practitioners.

Clinicians are now fully aware and in agreement that ADHD is common and treatable in all ages; however, most remain uncomfortable applying this information into practice. Feedback from primary care focus groups from symposia on the assessment of ADHD in Canada suggest that efforts that have gone into knowledge translation of adult ADHD have been insufficient in dealing with assessment and treatment issues of differential diagnosis and comorbidity. The first edition of the Canadian Attention Deficit Disorder Resource Alliance (CADDRA) practice guidelines2 addressed this issue by providing criteria to distinguish simple from complex cases of ADHD and recommended that only the latter be referred for consultation to a specialist. This strategy has been in large part successful, but it has not solved the problem of addressing service needs because most ADHD adults are complex cases, and there are few psychiatrists providing back-up expertise in adult ADHD.

Comorbidity is an area in which we have limited evidence to guide practice. Comorbidity dictates treatment response, and as long as clinicians remain uncomfortable with differential diagnosis and identification of other disorders, we will continue to be stymied in bringing treatment to those who need it. In practice, the clinically salient question is not just, “Does the patient have ADHD?” It is easy to teach practitioners to screen for ADHD and to write a prescription. The problem is that for most patients, the clinically salient questions are, “What else does this patient have?” and “How does this impact treatment?”  
The objective of this discussion is to frame an approach to translating expertise in differential diagnosis and management of comorbidity in ADHD into knowledge translation for primary care physicians and psychiatrists.  

 

Comorbidity of Psychiatric Disorders with ADHD

The National Comorbidity Survey Replication (NCS-R) was the first epidemiological study of adults to evaluate ADHD in the context of other psychiatric illnesses and disabilities.3 Kessler and colleagues3 demonstrated that the majority of adults with ADHD have a complicating clinically significant comorbid disorder, and up to 50% of patients with ADHD have a complicating mood or anxiety disorder (Slide 1). A significant fraction have substance abuse or impulse control.

 

 

 

 

Patterns of comorbidity between children and adults with ADHD are similar.4 Developmental disorders such as learning disabilities or autism spectrum disorders are more readily recognized and assessed in young children. By the same token, substance abuse, psychosis, and personality disorders emerge as adolescence unfolds. However, all of the available diagnostic interviews and rating scales have been either child based or adult based; what has never been tested is whether this migration of diagnoses with age is a function of the questions asked, changing environmental challenges across the life span, or actual age of onset. This means that our skills in diagnosing developmental disorders in adults or prodromes of adult syndromes in children is limited.

NCS data have also examined reverse comorbidity. What percentage of patients currently diagnosed or receiving treatment for another problem also have ADHD? A significant number of patients with substance abuse,5 mood or anxiety disorders,6 obesity,7 smoking,8 and up to 25% of prison inmates have ADHD.3 Although a sizable minority of patients in specialized treatment programs screen positive for ADHD, the NCS-R found that <10% of patients with another diagnosis had also been diagnosed as having ADHD. If ADHD is common but rarely diagnosed in specialized treatment populations at risk, the likelihood is that specialty clinics are failing to screen for or treat this condition.

A common anecdotal comment in the empirical work on ADHD is that patients who screen positive for ADHD in non-ADHD clinics overlap with the patients who have been treatment resistant. While it is difficult to provide safe and effective treatment of ADHD without evaluating comorbidity, it is also difficult to provide such treatment for a comorbidity in an ADHD patient without identifying and addressing the ADHD. Similarly, just as it is cost effective to screen for comorbid disorders in an ADHD clinic, the same applies for ADHD screening in clinics treating other problems. Comorbidity of ADHD impacts compliance, treatment persistence, insight, self-regulation, attendance, and treatment response.

Barkley and Murphy9 recently published preliminary findings examining the extent to which the high levels of comorbidity seen in ADHD populations is specific to this disorder or common to psychopathology in general. They found that adults with ADHD have significant comorbidities with depressive disorders, anxiety, alcohol use, cannabis use, other substance use, oppositional defiant disorder (ODD), conduct disorder, personality disorders, sleep problems, learning disabilities, and autism spectrum disorder. However, only dysthymia, cannabis abuse, and ODD were more comorbid in ADHD patients than in patients with other disorders. 

 

Differential Diagnosis

Education on ADHD in adults has attempted to simplify principals of differential diagnosis. In many lectures, presenters speak with confidence about the principals they use to rule in or rule out other disorders. Application of these principals in practice is difficult. There are several areas of differential diagnosis where the symptoms overlap between ADHD and another disorder is extensive, but treatment of the two disorders are distinct. The issues are not just academic, but are of considerable clinical importance (Slide 2).

 

 

 

 
 

Bipolar Disorder
Both bipolar disorder and ADHD patients may experience racing thoughts, hyperactivity, talkativeness, impulsivity, and distractibility. It is thought that bipolar disorder can be distinguished by the prominence of mood symptoms, and that grandiosity, racing thoughts, decreased need for sleep, and hypersexuality are more specific to bipolar disorder.10 Adults with ADHD often have problems with anger and mood lability. They have high energy and shortened hours of sleep. ADHD patients have “scattered minds”11 and complain of being unable to slow down or turn off their thoughts to attain cognitive relaxation. The thought disorder associated with ADHD is apparent to any skilled clinician who has to routinely take a history from these patients. ADHD patients who “take on the world” without compunction or second thoughts may certainly appear grandiose and may be considered to have an increase in goal-directed activity. Patients with ADHD may have episodic-like deterioration in functioning because living with ADHD is characterized by developmental hurdles, variable performance, and reactivity. The threshold between “bipolar” and “ADHD” for each particular symptom is on a spectrum where the cut-off for presence or absence varies between clinicians. ADHD and bipolar disorder are distinct syndromes that may coexist together. However, clear and distinct rules for differential diagnosis, establishment of comorbidity, and evidence-based guides to treatment and sequence of treatment remain controversial.

Oppositional Defiant Disorder
Like ADHD, ODD continues into adulthood with some degree of symptom migration. ODD is a distinct pattern of angry, resentful, and disagreeable stubbornness. In adults the color is the same; only the tone has changed. The need to externalize blame, control others, and argue is still there. A child who is oppositional and defiant tells an adult that he or she “cannot tell me what to do”. An adult who is oppositional argues with the doctor, fights the system, blames his boss, or blames his child’s teacher. At what point do we consider this ADHD and ODD in an adult, and at what point would we consider it a personality disorder? Flagrant disregard of authority is often alternatively perceived by adult psychiatrists as narcissistic or grandiose.

Sleep Disorders
Adults with ADHD often complain that they have problems going to bed, “turning their thoughts off,” and falling asleep. There are several clinically important questions in which research is in progress. For example, do these patients all have sleep disorders? Do sleep disorders worsen daytime cognitive functioning? Does ADHD cause or is ADHD associated with a sleep disorder? If children with sleep-disordered breathing have difficulty with attention, what does this imply for adults with severe sleep apnea? If a family doctor determines that a patient has problems with attention and a life-long history of a circadian rhythm sleep disorder, should that patient be treated with stimulants or hypnotics? Although the answers currently remain unknown, sleep research remains relevant to assessment and treatment of ADHD in adults.

Sluggish Cognitive Tempo
There is a distinct group of patients who have problems processing information. They have difficulty listening, following instructions, starting work, working efficiently, and often they “zone out.” They are not hyperactive or restless. These patients have sometimes been described as having “sluggish cognitive tempo,”12 but clinically they present as sluggish across the board. These patients seem to have a delayed response time, psychomotor retardation, hypoactivity, and an auditory lag that impacts pragmatic language. They come across as having a pseudo Parkinson-like syndrome. When one informs these patients that they have ADHD, they are surprised to find their diagnosis includes the term hyperactivity. Little work has been done on the adult outcome of this population. This is a distinct group of patients who would be difficult to identify in most adult settings.

Marijuana  
Many adolescents and adults use marijuana regularly.  Daily marijuana use not only increases problems with motivation, cognitive impairment, executive dysfunction, and attention, but it also limits the opportunity to intervene effectively for ADHD.13 Patients with ADHD and substance problems often hope to be treated with a pill and not a program of harm reduction. Provision of combined treatment is optimal, but the resources, skills, and evidence base to guide differential diagnosis and dual diagnosis treatment is scant.

Dysthymia
Diagnosis of dysthymia as a distinct mood disorder requires evidence of chronic low mood and two other symptoms, most of which are problematic in ADHD. It is easy to identify patients who have always been miserable but never had problems with attention or hyperactivity. It is easy to identify ADHD patients who have had hard lives but seem to keep fighting against all odds with an enthusiasm to keep trying. More difficult are those patients with long-term and severe damage to self-esteem, who have given up and are hopeless. These patients meet criteria for ADHD and dysthymia, and they are not uncommon. Current questions include: Should these patients be treated for a mood disorder? Does this dysthymia disappear with appropriate treatment of ADHD? What should be treated first? Would this be an appropriate target of psychological treatment? How does the presence of dysthymia moderate ADHD outcome? and How do stimulants moderate management of dysthymia?

Personality Disorders
There is a high rate of personality disorders in adults with ADHD.14 A personality disorder is a defined maladaptive and repetitive pattern of behavior and interaction with others. Apart from distinct personality clusters such as borderline, avoidant, or antisocial personality disorder, it is not uncommon to see a diagnosis of personality disorder not otherwise specified in this population. Patients with ADHD live with a condition that annoys others, and they do not always see why. This impacts personality development.

 

Difficulty of Differential Diagnosis of ADHD

The above examples are not meant to imply a statement regarding specific contentious issues that surround any differential diagnosis or comorbidity. Many other associated conditions, such as autism spectrum disorders or learning disabilities, are just as problematic. These examples have been selected to illustrate that even for the experts, differential diagnosis in adults with ADHD presents a challenge. Experts have the skill and the time to take a good developmental history and mental status evaluation, as well as the benefit of rating scales, collateral informants, and knowledge of the literature. The family doctor or psychiatrist in practice has to assess and manage ADHD without these advantages and often without easy access to expert consultation.

 

Lifetime Comorbidity as a Moderator of Outcome

Certain comorbid conditions, such as depression and drug use, are interesting in that the lifetime prevalence of the comorbidity greatly exceeds the current prevalence.15 In practice, the majority of adults with ADHD have had a significant problem with one or the other of these two difficulties at some point in their life, but a much smaller proportion are in the midst of such an episode at the time of assessment. The clinical implications of lifetime diagnosis for current management is unknown, although some research indicates that lifetime depression may be a significant moderator of treatment response for ADHD. In a four-treatment arm comparator study of paroxetine, paroxetine and dextroamphetamine, dextroamphetamine, and placebo (all with psychological treatment), patients who had a lifetime history of depression had significantly lower responses to dextroamphetamine.16

Subthreshold residual symptoms can be clinically significant, particularly when the patient is challenged with medications that unmask or trigger relapse of previous difficulties. There is greater comorbidity in cross-sectional samples of adults with ADHD than there is in prospective cases followed over time, suggesting a referral bias in which those who present in adulthood have both persistent ADHD symptoms and other problems as well. This has significant consequences for our understanding of developmental outcomes and the burden of illness represented by untreated ADHD.

 

Tools to Assess Comorbidity and Differential Diagnosis

The clinician needs tools that assist with screening and recording information on symptoms of possible comorbid conditions and that provide the information needed to recognize when further expertise or evaluation is needed to make a differential diagnosis. These tools must be user friendly and free of charge, and need to include both developmental and adult onset Axis I and Axis II conditions.  

In research, many of these issues are addressed through the use of structured diagnostic interviews. Diagnostic interviews are cumbersome tools in clinical practice and are limited in the spectrum of disorders and the ages that they cover. The Structured Clinical Interview for DSM-IV-TR (SCID-IV)17 does not include ADHD, ODD, learning disabilities, sleep disorders, autism spectrum, personality disorders, or Tourette’s syndrome. The Kiddie Schedule for Affective Disorders and Schizophrenia (Kiddie-SADS) is not written for use in adults, although it has been used for adults.18 Diagnostic interviews developed specifically for ADHD in adults do not address differential diagnosis from other disorders. There is no validated diagnostic interview appropriate to the spectrum of difficulties associated with ADHD in adults. Even more important, while structured diagnostic interviews have improved interrater reliability for research purposes, they have had minimal impact on improving interrater reliability in clinic settings. They are time consuming, require training, and do not address issues of differences between informants and settings.  

Gadow and colleagues19 have developed both self and informant Symptom Inventories that have been validated (www.checkmateplus.com). These scales facilitate knowledge translation of diagnostic expertise and DSM-IV criteria into the clinic setting, and promote research that can lead to further evidence-based guidelines. The scale is excellent and easy to use. The limitations of this measure is that it has to be purchased, although it is less costly than other measures and is the only adult-based DSM-IV checklist that includes developmental, Axis I, and Axis II disorders.   

In the revised CADDRA guidelines that will appear in the Fall of 2007, two new knowledge translation tools will be made available to facilitate assessment of comorbidity and differential diagnosis in ADHD. Both tools are clinician friendly, free of charge, available at www.caddra.ca, and is in the process of being validated. The Turgay Symptom Screener is a DSM-IV based scale for use by any informant to assist with diagnosis in children and adolescents.

The Weiss Symptom Record (WSR) is a way of collecting information on developmental, Axis I, and Axis II disorders in any age group and from any informant and an approach that is sensitive to child and adult disorders. The WSR has been developed for use in practice by clinicians. It is a simple way to record and evaluate clinical information about symptoms. The scale is designed to alert clinicians to clusters of problems that might otherwise be missed and allow for documentation of symptoms by different informants over time. It is of particular utility in assisting adult clinicians to assess developmental disorders in adults, and child clinicians in identifying early-onset adult disorders (such as personality disorder, eating disorder, or substance use). Items were chosen for high specificity with each diagnostic cluster to facilitate differential diagnosis. Research is currently in progress to examine predictive power of symptom clusters against clinician diagnosis. These measures are designed to provide a cross check on the mental status to improve comfort and confidence in recognizing when a case is complex to assist in identifying possible comorbid conditions that could represent a contraindication to treatment.

 

Conclusion

In the context of the raised expectations and tremendous enthusiasm for the therapeutic opportunity presented by adults with ADHD, it is important to understand that patients included in research data from clinical trials are a selected sub-sample in which significant comorbidities have often been excluded. Many of the patients observed in a publicly funded clinic would not be eligible for the clinical trials that form our evidence base. These patients are often disappointed to learn that for one or another reason they cannot take medication or that medication will not fix other more serious problems such as substance abuse, bipolar disorder, or personality disorder. ADHD in adults can be treatable, but it is not always treatable. The longer term future of our understanding of ADHD in adults will need to clarify the role of other syndromes in screening for who can benefit from what type of intervention and in what sequence (Slide 3). 

 

 

 

 

 

 

References

 

1. Faraone SV, Biederman J. Adult ADHD NOS: Is it a valid diosrder? Poster presented at: the American Psychiatric Association Annual Meeting; May 2005; Atlanta, Georgia.
2. Canadian Attention Deficit Disorder Resource Alliance. Canadian Practice Guidelines for ADHD. Toronto, Ontario: McCleery McCann; 2006.
3. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723.
4. Biederman J, Faraone SV, Spencer T, et al. Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry. 1993;150(12):1792-1798.
5. Wilens TE, Kwon A, Tanguay S, et al. Characteristics of adults with attention deficit hyperactivity disorder plus substance use disorder: the role of psychiatric comorbidity. Am J Addict. 2005;14(4):319-327.
6. Shekim WO, Asarnow RF, Hess E, Zaucha K, Wheeler N. A clinical and demographic profile of a sample of adults with attention deficit hyperactivity disorder, residual state. Compr Psychiatry. 1996;31:416-425.
7. Altfas JR. Prevalence of attention deficit/hyperactivity disorder among adults in obesity treatment. BMC Psychiatry. 2002;2:9.
8. Downey KK, Pomerleau CS, Pomerleau OF. Personality differences related to smoking and adult attention deficit hyperactivity disorder. J Subst Abuse. 1996;8(1):129-135.
9. Barkley RA, Murphy KR. Comorbid psychiatric disorders in adults with ADHD. The ADHD Report. 2007;15(2):1-7.
10. Tillman R, Geller B. Controlled study of switching from attention-deficit/hyperactivity disorder to a prepubertal and early adolescent bipolar I disorder phenotype during 6-year prospective follow-up: rate, risk, and predictors. Dev Psychopathol. 2006;18(4):1037-1053.
11. Adler LA, Florence M. Scattered Minds. New York, NY: Putnam; 2006.
12. Hinshaw SP, Carte ET, Fan C, Jassy JS, Owens EB. Neuropsychological functioning of girls with attention-deficit/hyperactivity disorder followed prospectively into adolescence: evidence for continuing deficits? Neuropsychology. 2007;21(2):263-273.
13. Flory K, Milich R, Lynam DR, Leukefeld C, Clayton R. Relation between childhood disruptive behavior disorders and substance use and dependence symptoms in young adulthood: individuals with symptoms of attention-deficit/hyperactivity disorder and conduct disorder are uniquely at risk. Psychol Addict Behav. 2003;17(2):151-158.
14. Philipsen A. Differential diagnosis and comorbidity of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) in adults. Eur Arch Psychiatry Clin Neurosci. 2006;256(Suppl 1):i42-i46.
15. Spencer TJ, Biederman J, Mick E. Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol. 2007;32(6):631-642.
16. Weiss M, Hechtman L. A randomized double-blind trial of paroxetine and/or dextroamphetamine and problem-focused therapy for attention-deficit/hyperactivity disorder in adults. J Clin Psychiatry. 2006;67(4):611-619.
17. First MB, Spitzer RL, Gibbon M, Williams JBW. SCID-I, Clinician Version. Washington, DC: American Psychiatric Press; 1997.
18. Biederman J, Monuteaux MC, Mick E, et al. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychol Med. 2006;36(2):167-179.
19. Gadow K, Sprafkin J, Weiss M. Manual for the Adult Self Report Inventory and Adult Symptom Inventory. Stony Brook, New York: Checkmate Plus; 2004.

 

 

 

 

 

 

Therapeutic Management

 

By Mark A. Stein, PhD, ABPP

 

 

 

Dr. Stein is professor at the Institute for Juvenile Research in the Department of Psychiatry at the University of Illinois at Chicago, and director at the HALP Clinic/ADHD Research Center in Northbrook, Illinois.

 

Disclosures: Dr. Stein receives research support from Cephalon, Eli Lilly, McNeil, and Novartis; and receives honoraria and compensation for service on the advisory boards of Cortex, McNeil, Novartis, Pfizer, and Shire.

 

 

 

Introduction

 Although much is known about attention-deficit/hyperactivity disorder (ADHD) in children, there is a lot that remains unknown about diagnosing and treating ADHD in adults. The first pillar of treatment is a good evaluation, followed by development of a specific treatment plan that includes targeting associated impairments and building upon the individual’s unique strengths or protective factors. This discussion will focus on therapeutic management, including the implications of comorbidity on management of ADHD in adults, as well as some of the key treatment options.

 

Therapeutic Management    

Review of Evaluation
Although the word treatment typically brings to mind medication or psychosocial therapy, treatment of ADHD really begins at the evaluation stage. This first stage of treatment involves reviewing the patient’s symptoms and impairment; what was learned about the patient during the diagnostic evaluation, including his or her particular strengths, protective factors, weaknesses, and possible mimics that were ruled out in explaining the symptoms and impairments.  

A frequent occurrence in developing a treatment plan is the decision that more information is needed prior to proceeding with treatment. For example, a physician evaluating a college student may request a neuropsychological or psychometric assessment to determine if accommodations are warranted. If a patient showed elevated blood pressure during the exam, or strong family history of heart disease or syncope, the physician may want to obtain a cardiology consult. If the patient seems unsatisfied with his job, a vocational assessment may be helpful. Hence, the next step after an initial evaluation may be referral for further consultation or evaluation.  

Reviewing data from the evaluation and what one has learned about the patient is helpful in setting the stage for developing the treatment plan. Taking the time to perform a careful and comprehensive evaluation may enhance future treatment compliance, as it instills confidence that the treating physician understands the problems at hand and cares about the patient’s well being. Taking the important step of reviewing the evaluation reinforces to the patient that the physician is treating a patient and not a diagnosis. Furthermore, it provides an opportunity for the physician to educate the patient about his disorder, and to describe how treatments are delivered, monitored, and revised.

Educating the Patient
It is important to inform the patient of both what is currently known about ADHD and what is not known. It is increasingly the case that people self-diagnose their own ADHD based on Internet information and popular books1 about the disorder; however, many of these sources propagate myths. For example, some sources claim that people with ADHD are creative and fun to be around, but these sources often do not focus on the cumulative impairments and frequent comorbidity associated with the disorder. Others claim that most people tend to grow out of ADHD. In reality, many people do not outgrow ADHD, although often hyperactivity symptoms decline or become more subtle.2 Therefore, it is important to educate patients about what is and is not known about ADHD, including the limits of our current scientific knowledge about this disorder (Slide 1).

 

 

 

 

Issues Surrounding Comorbidity
While there are several psychiatric comorbidities that are commonly associated with ADHD, there are also issues that result from having ADHD that are often mistaken for comorbidities. For example, a patient with ADHD who is doing poorly academically and has been doing poorly socially for many years is likely to be demoralized and frustrated. While the symptom may certainly look like a primary mood disorder, this is different from major depression. Often, these individuals do not respond to antidepressants, which are typically tried first with adults with mood and ADHD symptoms. However, they typically display rapid improvements in mood when their ADHD symptoms are appropriately treated or when placed in a different environment where ADHD symptoms are less of a problem.   

 

Development of a Treatment Plan

Developing a treatment plan involves selecting an initial treatment strategy, as well as a time frame and a method with which to evaluate the effect of that particular treatment on the patient’s chief complaint and primary area of impairment. This usually involves monitoring several symptoms at once, such as attention, mood, and family functioning.

Once any remaining questions are answered, the next step is to define the targets outcomes and how they will be measured. Examples of target outcomes for an ADHD patient include impulsivity at work or at school; a secondary target may be mood, sleep, or the effect on the family. All of the treatment options should be reviewed, and the one with the most favorable risk-benefit ratio selected (Slide 2).

 

 

 

 

Treatment Options   

Pharmacotherapy
The Food and Drug Administration-approved medication choices are the stimulants mixed amphetamine salts or dexmethylphenidate, or the nonstimulant atomoxetine. There are numerous other medications that are effective in treating ADHD as well (Slide 3). Although there are many effective agents, there are few long-term studies and very few direct comparative studies on which to base decisions.

 

 
One of the choice points is long-acting versus short-acting agents. While patients often request immediate-release agents, many clinicians are uncomfortable prescribing them to ADHD patients due to their difficulties with time management. Certainly the more complex the therapeutic regimen, the more difficulty a patient will have in following it, and once-a-day treatments are often easier to follow. However, for many individuals the duration of treatment is too limited even with the long-acting treatments, resulting in multiple doses even with these agents.    

Psychosocial Interventions
In terms of psychosocial treatments for ADHD, one must consider the fit between the patient, expectations, and the environment. Direct psychosocial treatment can be aimed to promote that “fit” by combining learning-based or behavioral treatments with appropriately selecting environments to promote their strengths and minimize their individual weaknesses. It is also beneficial to help the patient identify what their strengths are and help them find situations where their strengths are utilized. For example, if a patient has good social skills, it is important to encourage involvement in an occupation and/or environment where that skill is valued.

There are very limited data on psychosocial interventions that directly target ADHD, although early reports are encouraging.3 In one of the few controlled studies targeting adults with ADHD specifically, Safren and colleagues4 examined the effect of combining medication with cognitive-behavioral therapy (CBT) in 31 adults with ADHD.  At outcome, the CBT plus medication group  displayed  fewer ADHD symptoms, less depression and anxiety, and overall severity was less than those treated with medication alone. Many of the psychosocial interventions that have been empirically validated address the comorbid condition, such as mood or anxiety disorders. For example, it is very common to combine medication treatment of ADHD with CBT for comorbid anxiety or mood disorders, or with coaching, marital, or family therapy. Other psychosocial treatments, such as coaching, are helpful to adults with ADHD, although these services are difficult to obtain in some areas. Usually, contacting ADHD support groups such as CHADD or ADA is helpful in finding local professionals with this expertise.

There are several recommendations for psychosocial treatment that have not been evaluated specifically for ADHD, but are assumed to be helpful in that population because they are helpful to most other people. These include lifestyle improvements like maintaining a daily exercise regimen.

 

Frequent Clinical Dilemmas and Decision Points

Mood Symptoms
Approximately 50% of adults with ADHD have mood symptoms. A common question is which to treat first: the ADHD or the mood symptoms. A treatment strategy should be developed in anticipation of suboptimal  response to the first agent. ADHD specialists typically see patients who have previously been diagnosed or treated for mild depression or dysthymia. For patients who present with a clear history of  ADHD, it is often best to treat the ADHD first, while monitoring the mood symptoms in response to the treatment.

In a primary care setting or one where the practitioner has not had experience with ADHD, the challenge is to identify  someone with previously undiagnosed ADHD. Often, ADHD diagnoses are missed because the comorbid disorder is more prominent or is one that the practitioner is more accustomed to screening for based upon their own training.

Some of the greatest clinical successes are patients who have ADHD and mild mood symptoms or demoralization, where the ADHD has not been previously treated. When the ADHD is treated optimally, the mood symptoms often respond.5 Overall, it may be  best to select one treatment and then monitor both outcomes rather than combine several medications at once so that treatment response is not obscured by multiple agents (Slide 4).

 

 

Personality Disorders
Another common presentation is when an individual reports ADHD symptoms but also has a very prominent personality disorder that clearly affects his relationships above and beyond the effects of the ADHD symptoms. This is a difficult management situation because these patients are highly invested in ADHD treatment being the sole solution to their problem and have little motivation for changing their personality despite the obvious negative impact on their interpersonal relationships. In cases like this, medication is  a very small part of the necessary treatment plan.

Learning Disorders
Many individuals with poor attention also have learning disorders. In adults, especially, this is often not identified. Medication may help, but unless the patient understands what their learning disorder is and receives additional supports, they are going to continue to struggle.

 
Mild or Subthreshold  ADHD
Some of the most successful cases are patients with sub-threshold or mild ADHD. The clinical question is, “when does one treat patients with very mild symptoms or those who do not have a childhood history of ADHD symptoms with medication?” A key to making this judgment is the degree of impairment judged to be associated with the ADHD symptoms. Generally, it is much more difficult to monitor attention as opposed to hyperactivity and impulsivity symptoms, especially based on self-report. It is often useful to obtain other measures of their functioning and to elicit observations from other individuals who know the patient.

Substance Use Disorder
A common clinical presentation is the individual who presents with a substance use disorder and a history of ADHD. Many adolescents and adults with undertreated or poorly treated ADHD develop substance abuse disorder.6 In this case, the critical question is which treatments to select given that there is some risk of abuse and diversion with stimulants. On the other hand, this is a symptom constellation with poor prognosis and usually limited motivation for treatment or for tolerating initial treatment failures. The choices will depend on how well the physician knows the patient and what type of relationship they have. There are some data that suggest that one can treat the ADHD with stimulants without exacerbating the substance abuse,7 although there is need for further study in this controversial area. There are also several medication options besides stimulants that have decreased “likeability” such as atomoxetine or that are very difficult to abuse because of their delivery system. Once again, educating the patient about the course of the disorder and strategies for evaluating treatment response should increase the likelihood of a successful strategy even if the initial treatment choice is not successful.

 

Conclusion

There is now increased awareness of ADHD in adults and many more treatment options for ADHD. However, there is a very limited scientific literature for selecting among different treatment options, as the majority of treatment studies have compared a single medication to a placebo, rather than comparing several medications or using crossover designs. In addition, the populations selected for ADHD  studies may differ in several ways, including degree and presence of comorbidity, from patients who are treated in clinics.

On a positive note, it seems that adults are better able to tolerate side effects than children. It may be that many of the adverse events observed in children in response to stimulants, such as loss of appetite and insomnia, appear to be less significant in the adult populations. However, adults are certainly a challenge because of the wide range of impairments they display and because of their increased risk for medical comorbidities. Unlike children, they must administer their own medications and seek appropriate and effective psychosocial treatments which are often not easy to find.

 

References

1. Hallowell EM, Ratey JJ. Driven to Distraction. New York: Pantheon Books; 1994.
2. Klein R, Mannuzza S. Long-term outcome of hyperactive children: a review. J Am Acad Child Adolesc Psychiatry. 1991;30:383-387.
3. Rostain AL. Treating comorbid ADHD in adults: mixed results in recent clinical trials. Curr Psychiatry Rep. 2006;8(5):391-392.
4. Safren SA, Otto MW, et al. Cognitive-behavioral therapy for ADHD in medication-treated adults with continued symptoms. Behav Res Ther. 2005;43(7):831-842.
5. Barkley RA, Anastopoulos AD, et al. Adolescents with ADHD: patterns of behavioral adjustment, academic functioning, and treatment utilization. J Am Acad Child Adolesc Psychiatry. 1991;30(5):752-761.
6. Biederman J, Wilens TE, et al. Diagnosis and treatment of adults with attention-deficit/hyperactivity disorder. CNS Spectr. 2007;12(4 Suppl 6):1-15.
7. Schubiner H. Substance abuse in patients with attention-deficit hyperactivity disorder: therapeutic implications. CNS Drugs. 2005;19(8):643-655.

 

 

Pharmacologic Treatment of ADHD and Comorbidity in Adults

 

By Jeffrey H. Newcorn, MD

 

 

 

Dr. Newcorn is associate professor of psychiatry and pediatrics and director of the Division of Child and Adolescent Psychiatry, Department of Psychiatry, at The Mount Sinai School of Medicine in New York City.

 

Disclosures: Dr. Newcorn is a consultant/advisor to and receives honoraria from Cortex, Eli Lilly, Lupin, McNeil, Novartis, Pfizer, and Shire.

 

Neurobiological Basis of ADHD and Treatment

Attention-deficit/hyperactivity disorder (ADHD) is a neurobiologically based disorder characterized by functional abnormalities in a coordinated group of brain regions that govern executive and inhibitory functions, including the prefrontal cortex, striatum, thalamus, and cerebellum. This is supported by findings from neuroimaging studies that show differences in glucose utilization during positron emission tomography scans, and blood oxygen levels during magnetic resonance imaging (MRI) scans in adults with ADHD. In addition, studies that use radioactive ligands, proteins that competitively bind to receptors, in conjunction with positron emission topography have demonstrated differences in the density of presynaptic dopamine transporters and/or postsynaptic dopamine D2 receptors in those with the disorder.

 
ADHD is often treated with psychostimulant medications, which work by binding to dopamine transporters in striatum, and norepinephrine (NE) transporters in several brain regions. The percentage of dopamine transporters bound with medication following an oral dose of methylphenidate (MPH) increases in a dose-dependent fashion, and levels off at a dose that is associated with robust clinical response.  MPH and amphetamine differ somewhat in their receptor binding characteristics. Amphetamine increases NE by enhancing release as well as blocking reuptake. Stimulant treatment increases activation in brain regions implicated in attention and executive function in subjects with ADHD scanned with MRI while performing tests of inhibitory control. The degree of activation in a brain region reflects the level of oxygen in the blood flowing to that region, which is presumed to reflect the degree to which a particular brain region is used in performing the task being studied.  
 
The nonstimulant atomoxetine, approved by the Food and Drug Administration for the treatment of ADHD, binds selectively to the NE transporter, thereby increasing NE diffusely and DA in the prefrontal cortex. Preliminary data indicate that atomoxetine may have similar effects as stimulants in increasing catecholamine levels and/or activation profiles in several brain regions.
 

Pharmacologic Treatment of ADHD in Adults

In general, all medications that are useful in treating ADHD in children are also effective in adults. However, FDA approval of medications for treatment in adults is a relatively new phenomenon. The first medication approved by the FDA for adult ADHD was atomoxetine, in 2002. Atomoxetine remains the only approved nonstimulant for ADHD in adults or children.  

Dextromethylphenidate extended-release (ER) and mixed amphetamine salts ER are both FDA approved for adults. The latter is approved at a maximum dose of 20 mg in adults, compared to 30 mg in children. OROS MPH is approved for use in children and adolescents, but is the most frequently used MPH formulation in adults.

Effect sizes of approved medications in adult ADHD are approximately half what they are in children. There are a variety of reasons for this, including the higher placebo response rate and, in some cases, the lower maximum approved dose in adults. Effect sizes of long-acting stimulants in controlled registration trials for adult ADHD ranged from slightly less than 0.5 to 0.8, depending on the measure examined and the dose used.1,2 Effect sizes were lower at doses that were ultimately approved, but higher for doses that were studied but did not receive approval. In other studies in which more robust doses of stimulants were used, effect sizes have been reported to approach or exceed 1.0. For example, Spencer and colleagues3 found the effect size of methylphenidate immediate release (IR) treatment in adults with ADHD to be 1.4 when the mean dose used was 1.1 mg/kg/day administered on a TID schedule.

Some medications that are used off-label for ADHD are approved by the FDA for other indications in adults, including bupropion,4 guanfacine,5 and modafinil.6,7 Bupropion has the most supporting data of any of the non-approved treatments in adults. Use of guanfacine and modafinil in adults is mainly extrapolated from results of studies in children.

Medications that treat conditions other than ADHD can generally be used to treat those same conditions when they are present with ADHD. These include antidepressants, anxiolytics, atypical antipsychotics, and mood stabilizers.

 

Benefits of Longer-Acting Treatments

Much of the recent research on treatment of ADHD has been with longer-acting agents. Because attention and self-regulatory control are required for a variety of activities and not only academic and occupational functions, and because adults often work longer and later than children, it stands to reason that they would require a longer duration of medication effects (up to 12–16 hours). Lack of medication coverage at any time during the day can negatively affect a variety of functional domains, such as motivation, decision-making, and cognitive and affective functions. Deficits in these areas impact negatively on social relationships, cognitive and occupational functions, parenting responsibilities, driving, and evening study or work time.8  

Using short-acting stimulant treatments as the primary modality requires multiple daytime doses to cover the same time period. This is likely to result in less adequate adherence to treatment. IR formulations of stimulants may also carry a higher risk for diversion or abuse than the long-acting formulations because they produce more rapid escalations in plasma level and are cleared relatively quickly. This is a concern in treating adults, particularly college students. Yet, despite the benefits of long-acting treatments, and the various concerns often raised regarding use of shorter acting agents as primary agents, many adults seem to prefer shorter-acting treatments, because they feel they can better target activity to a particular task or time of day.1

 

Dosing of ADHD Medication Treatments 

Amphetamines

Amphetamines are available in IR and ER preparations. The ER formulation of mixed amphetamine salts (MAS XR) last ~10–12 hours, while the IR formulations of mixed amphetamine salts and d-amphetamine last ~6 hours (Slide 1).

 
 

 

The highest approved daily dose of MAS XR is 20 mg, although doses of up to 60 mg were studied in premarketing clinical trials1 and are often used in clinical practice. The approval of only the 20-mg dose reflects the FDA finding that differences in clinical response at higher doses in forced dose titration trials were not large enough to justify the potential for increased adverse effects. This illustrates the challenge involved in demonstrating that doses routinely used in clinical practice with adults, with which many clinicians find the greatest level of improvement, are labeled as being incrementally effective based on clinical trials data.

 

 
The efficacy of MAS XR was evaluated in 255 adults with ADHD in a 4-week, randomized, double-blind, placebo-controlled study.1 Treatment was associated with a statistically and clinically significant reduction in ADHD symptoms, as assessed by the ADHD Rating Scale at endpoint, with the greatest improvement in symptoms occurring in the 60-mg dose group. A post-hoc analysis suggested a trend for linear dose response. Adults with severe symptoms showed significantly greater improvement with the 60-mg dose of MAS XR compared with placebo and the 20-mg dose, and numerically but not statistically greater improvement compared to the 40-mg dose. There was a dose-response relationship at week 4 for ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. 

A new amphetamine, lisdexamfetamine (LDX), has just recently received FDA approval for children 6–12 years old.  This medication is of particular interest in treating adults but published data to support its use are not yet available.  

 
Methylphenidate
MPH IR formulations last 3–4 hours, intermediate long-acting formulations last about 8 hours, and dextromethylphenidate XR and continuous-release OROS MPH last 10–12 hours (Slide 2). MPH is approved with a maximum labeled dose of 60 mg, with the exception of OROS MPH, which is approved at a maximum dosage of 72 mg in adolescents. A recent double-blind, placebo-controlled study of OROS MPH in adults with ADHD utilized a mean dose of  80.9±31.8 mg (0.99±0.32 mg/kg) for OROS MPH,9 which illustrates the large gap between the maximum FDA-approved dose and the dose that is likely to produce the most robust response.

  

 

 

The current approach to treating adult ADHD with relatively higher doses dates to the mid-1990s, when a study utilizing MPH IR in adults with ADHD showed a robust drug response rate. The drug was given at 1 mg/kg, on a TID schedule. This dose is entirely consistent with findings from pediatric studies,8 but higher than the average daily dose of ~0.6 mg/kg/day previously utilized in studies in adults, in which there was a more modest response.3

Similar to MPH IR, dosing of OROS MPH changes with age. As people get older and larger, they require higher absolute doses of stimulants, although this often computes to a lower mg/kg dose level. In the adolescent study of OROS MPH, the mean dose was ~0.85 mg/kg/day, and ~65% of the patients were titrated to 54 or 72 mg/kg/day.10 In contrast, in the pivotal premarketing trial11 conducted in patients 6–12 years of age, the mean mg/kg dose was ~1.15, although the absolute dose was lower than in the adolescent study.

OROS MPH was evaluated in a flexible dose study in 141 adults with ADHD.11 Almost 50% of patients in the treatment group had a 30% reduction and ~30% had a 50% reduction on the Adult ADHD Investigator System Report Scale (AISRS); ~40% achieved a CGI-I score ≤2. Improvement in ADHD symptoms with MPH treatment was significantly different from placebo beginning at week 3.

 
Dexmethylphenidate ER was tested in 5-week parallel group design trial in adults with ADHD comparing placebo with 20 mg, 30 mg, and 40 mg doses under double-blind conditions.12 All three dosages were more effective than placebo, reducing mean ADHD-RS total scores by 36% to 46% versus 21% with placebo. The highest dose that received FDA approval was 20 mg because the study failed to show incremental improvement between the 20 and 30 mg doses and the 30 and 40 mg doses. However, the study may not have been adequately powered to determine these contrasts.
 

Atomoxetine
Atomoxetine is dosed by mg/kg weight in all age groups, thus there is no issue with difference in weight-related and absolute dose in adults (Slide 3). The recommendation is to begin with 40 mg in adults,13 although many clinicians begin with 25 mg and titrate the dose upward more slowly, often with weekly dose adjustments, to reach a target dose of 100 mg. The effect size of atomoxetine in double-blind studies in adults was relatively modest, at slightly less than 0.4. This lower effect size may reflect the higher placebo response frequently seen in adults or other factors related to the study design, although it is also possible that the medication could be less effective in adults than children.14

 

 

 

 

 

Interestingly, there seemed to be incremental improvement with extended usage of atomoxetine in an open-label extension study.15 This raises the question about how atomoxetine should be dosed, over what period of time, and how to best measure improvement in adults. Of note, many of the domains of greatest interest in adults are more difficult to track. They are not quite as obvious as they are in children, and it may take a while to fully appreciate changes following treatment. The idea that medications that are relatively rapid in their onset of effect may require more extended time before showing incremental improvement is intriguing, and speaks to the complexities in appreciating, tracking, and measuring treatment response in adults with ADHD.

Bupropion
The mixed dopaminergic noradrenergic agent bupropion is approved for depression in adults and used off-label for ADHD in children and adults. Wilens and colleagues4 reported a ≥30% reduction from baseline in adults with ADHD. Bupropion could be a good choice for patients with ADHD and comorbid depression because it is approved for depression with has demonstrated activity in ADHD.  

 

Treatment of ADHD and Comorbidity in Adults  

Substance Abuse 

Risk for substance abuse is a particular concern in adults with ADHD since stimulants are schedule II controlled substances and longitudinal studies of children with ADHD have found an increased risk for substance abuse. Several open studies and case reports but only a handful of controlled studies address the question of how to treat individuals with ADHD and comorbid substance abuse. Findings have been mixed, with separation from placebo in some studies but not others.16,17 Some preliminary findings suggest that substance abuse improves when ADHD is successfully treated.

 
A related question is whether it is possible to develop new medications for ADHD with low potential for abuse and diversion (ie, giving or selling the medication to others). Most diversion seems to be motivated by the desire to improve cognitive function and not abuse per se; however, stimulants have potential for abuse, primarily when administered intravenously (IV) or intranasally (IN). Self-administration studies in animals and likeability studies in humans have demonstrated that atomoxetine has very low abuse potential.18 Animals do not self-administer the drug when given a choice, and human substance abusers do not particularly favor it. Also, it is not associated with feelings of euphoria.
 
LDX is a prodrug of d-amphetamine, in which d-amphetamine is covalently bound to the amino acid l-lysine. LDX is inactive until it is metabolized by gastrointestinal enzymes, which cleave the covalent bond and release d-amphetamine into the bloodstream. Thus, even if the drug is used via IV or IN, it does not produce the rapid increase in plasma level observed with IV or IN administration of other stimulants, which would considerably lower its potential for abuse. Likeability studies conducted with LDX in adults who abuse stimulants show that in moderate or relatively high oral doses, LDX produces little euphoria and is not considered as desirable as d-amphetamine for abuse purposes.19
 
Comorbid Anxiety
Understanding the relationships among ADHD and comorbid disorders is of particular importance in treating adults with ADHD. The clinical presentation of ADHD and comorbid anxiety disorder is illustrative of this point. Individuals with ADHD, who often have impairments in performance and repeated experience of failure, might reasonably be expected to approach new situations with a certain degree of fear and trepidation. Hence, it stands to reason that some degree of anxiety may be secondary to the experience of having ADHD. A related question is whether this anxiety improves if the ADHD is treated or whether it represents an independent problem.
 

The notion that anxiety symptoms could be secondary to ADHD would only apply if the anxiety were restricted to performance situations or other contexts in which impairment from ADHD is evident.

One study examined the rates of improvement in children with ADHD and anxiety disorders after treatment with stimulant medication (MAS XR).20 ADHD symptoms improved as would be expected without comorbidity. In addition, anxiety symptoms improved in some subjects, but remained high in others. Overall, there was not a statistically significant change in anxiety symptoms with treatment, but the study was not adequately powered to detect such changes.

Another recent study examined the effects of atomoxetine on both ADHD and anxiety symptoms in children and adolescents with ADHD and comorbid anxiety disorders.21 Reduction in treating ADHD symptoms was more or less equivalent to that observed in patients without comorbidity, but with a relatively higher effect size of 1.0 (compared with 0.7 in previous studies of ADHD youths who mainly did not have anxiety disorders). There was statistically significant improvement in anxiety symptoms, albeit with a lower effect size of 0.5. These findings are of considerable clinical interest. More extensive study is required to determine whether atomoxetine is more effective in treating ADHD in individuals with comorbid anxiety disorders, and whether it is a parsimonious treatment for anxiety in these patients. 

 

Conclusion    

ADHD is frequently present in adults with other psychiatric disorders. Some of these conditions are of specific interest in adults (eg, substance use disorder) or present somewhat differently in adults (eg, mood disorders) than in children. As a corollary, it is important to consider whether ADHD is also present in adults with other psychiatric disorders, since these can often mimic or mask ADHD symptoms.  

As a general rule, all treatments that are effective for ADHD in children are effective in adults as well, and all three medication classes which are approved for ADHD in children are also approved for use in adults. However, not all formulations are approved in adults. Effect sizes for treatment of ADHD symptoms are approximately half of what they are in children, when approved doses are examined.

Few studies have examined the effectiveness of medication in ADHD plus comorbidity, and none are in adults; thus it is necessary to extrapolate from data in children and  non-comorbid populations. When symptoms of multiple disorders are present, it is important to prioritize the approach to treatment, giving most attention to the disorders that are most severe and associated with the highest degree of impairment. If it is likely that the comorbid condition is a result of ADHD, or if ADHD is the most impairing condition, one should proceed with treatment of ADHD first. However, in cases where the comorbid disorder is highly impairing, it is often imperative to treat the comorbid condition first.   

 
There has been an explosion of data regarding medication treatment of ADHD over the past 10 years, and this is especially true with regard to treatment of adults. Unfortunately, there are few studies that provide empirical data regarding treatment of ADHD and comorbidity, as the large majority of research is conducted in non-comorbid subjects. Important next steps are to more closely study the treatment of ADHD and comorbidity, with particular attention to presentation in adults, and to develop specific approaches relevant to this under-identified and under-treated population.
 

 

References

1. Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006;11:625-639.
2. Spencer TJ, Adler LA, McGough JJ, et al. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61(12):1380-1387.
3. Spencer T, Biederman J, Wilens T, et al. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57(5):456-463.
4. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry. 2005;57(7):793-801.
5. Taylor FB, Russo J.     Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2001;21(2):223-228.
6. Turner DC, Clark L, Dowson J, et al. Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2004;55(10):1031-1040.
7. Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults.J Child Adolesc Psychopharmacol. 2000;10(4):311-320.
8. Barkley RA, ed. Attention-deficit Hyperactivity Disorder. A Handbook for Diagnosis and Treatment. 2nd ed. New York, NY: The Guilford Press; 1998:594-597.
9. Biederman J, Mick E, Surman C, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006;59:829-835.
10. Wilens TE, McBurnett K, Bukstein O, et al. Multisite controlled study of OROS methylphenidate in the treatment of adolescents with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 2006;160(1):82-90.
11. Wolraich ML, Greenhill LL, Pelham W, et al. Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108(4):883-892.
12. Robinson MR, Keating GM. Dexmethylphenidate extended release in attention-deficit hyperactivity disorder. Drugs. 2006;66:661-668.
13. StratteraTM [package insert]. Indianapolis, IN: Eli Lilly and Company; 2002.
14. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53(2):112-120.
15. Adler LA, Spencer TJ, Milton DR, Moore RJ, Michelson D. Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis. J Clin Psychiatry. 2005;66(3):294-299.
16. Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol. 2002;10(3):286-294.
17. Riggs PD, Hall SK, Mikulich-Gebertson SK, et al. A randomized controlled trial of pemoline for attention-deficit/hyperactivity disorder in substance-abusing adolescents. J Am Acad Child Adolesc Psychiatry. 2004;43(4):420-429.
18. Gasior M, Bergman J, Kallman MJ, Paronis CA. Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys. Neuropsychopharmacology. 2005;30(4):758-764.
19. Jasinski DR, Krishnan S. Abuse liability of intravenous L-lysine-damphetamine (LDX). Presented at: The 68th Annual Meeting of the College on Problems of Drug Dependence; June 2006; Scottsdale, Arizona.    
20. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2005;44(5):418-427.
21. Geller D, Donnelly C, Lopez F, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry. In Press.

 

 

 

 

Question-and-Answer Forum

 

Q: Increasing publicity about ADHD treatment has raised expectations in many people who have long-standing failures, that the problem may be simple and responsive to a quick fix. What recommendations would make for clinicians in negotiating this?

Dr. Stein: It begins with a careful evaluation, which results in a comprehensive diagnosis and treatment plan that describes the symptoms, impairments, and strengths of the individual, and whether the symptoms meet the profile of ADHD. In some cases symptoms are due to a condition that “mimics” ADHD or are better explained by  another disorder. For example, we had a case of a first-year medical student who had taken an online questionnaire about ADHD symptoms and thought he had ADHD. In actuality, the student had a very mild learning disability that explained why he has was having academic  difficulties despite his best efforts. In cases like this, psychometric testing can be helpful in determining the extent of his learning disability. In the clinical setting, we often define attention as a cognitive process based upon a behavioral rating or a self-report, which is often very far removed from the real phenomenon.

Dr. Newcorn: One of the problems we have in identifying ADHD in adults as compared to children is that we do not know how to account for personality development. There is emerging literature on personality disorders and personality styles in ADHD youths followed over time. It is clear that there are highly increased rates of antisocial disorders, a number of other personality disorders, and certain personality styles. The issue of “quick fix” versus more enduring or embedded kinds of problems is particularly well understood in that context. Certainly if a person has a life-long history of ADHD, he/she has an entire personality that has grown up around it. The idea that there is actually a neurobiologically-based diagnosis that offers an explanation for a variety of these problems can be quite powerful, and this recognition can add a very important dimension to evaluating and treating adults with ADHD. It also suggests that the way adults are likely to experience themselves and rate their level of improvement is different than in children. For example, data from long-term studies of treatment response in adults with ADHD suggest there may be incremental improvement over time. But whether it is actually incremental improvement, or rather a change in being able to identify and self-report improvement that is only appreciated incrementally over time, is an interesting point to consider.

 

Q: Cinicians often say that they have to use higher medication doses than the label indicates to achieve the best response. What do you recommend in this instance?

Dr. Newcorn: Although clinical realities may require dosing that exceeds the labeled maximum, it is important not to be cavalier about prescribing in this manner. While some people are going to need higher doses in order to be treated effectively, it is important not to compromise safety. When I dose above the label, I try to stay within the dose range that has been studied in clinical trials (and to be aware of whether the various doses studied were found to be safe). While doses above the label may not have been deemed more effective at the group level, if they were determined to be relatively safe, the risk-benefit ratio would be in favor of at least trying the higher dose. At the same time, I am mindful that some patients respond better to one treatment for ADHD than another. So, if the dose has to continuously be increased, it is important to consider the possibility that the patient is only a partial responder to the medication being used, and try a different medication. It may be possible to use another medication equally or more effectively, and at a lower dose.

 

Q: Clinicians encounter problems differentiating ADHD from comorbid disorders. There is risk in providing improper treatment for another condition when one focuses on ADHD incorrectly, as well as in not treating ADHD properly. What can be done to optimize accurate diagnosis?

Dr.  Weiss: Historically, whenever new information comes along that provides a new therapeutic opportunity—a new psychotherapy, a new medication, or a new diagnostic group in a different age spectrum— there follows an initial period of enthusiasm. Clearly, recognizing and being able to treat ADHD in adulthood is an important new therapeutic opportunity. The availability of screening scales that are in the public domain has improved awareness of the problem, and has also raised patient expectations. Many patients have the mistaken impression that if they have ADHD, and it has not been diagnosed, then treatment may also cure their learning disability, substance problem, personality difficulties or mood disorder. When they learn that this is not the case, they can be disappointed.

Dr.  Stein: One must also consider whether there is an impairment associated with the ADHD or the comorbid disorder. About half of the adults who come to our adult ADHD clinic do not have ADHD. Some of them have another disorder that is worse than ADHD, but there is also a percentage of patients who do not meet the impairment criteria for ADHD. They may self-identify as having a few subthreshold symptoms, but they really are doing well in life. The clinician must define the boundary between what is performance enhancement versus what is a psychiatric disorder. A disorder is accompanied by symptoms and impairment.

Dr.  Newcorn: If clinicians assume that they will achieve the same exact effects in adults as in children, they may be disappointed. It could be that medications are less effective in adults than children. But one also needs to consider possible psychological factors that could contribute to the enduring nature of ADHD in adults. Thus, it is possible that psychosocial interventions will become increasingly important in treating adults with ADHD in the future, regardless of whether or not they are also taking medication.