Addressing the Challenges of Treatment Resistant ADHD in Adults

Psychiatric TimesVol 35, Issue 7
Volume 35
Issue 7

This CME identifies the sources of treatment-resistant ADHD in adults and focuses on preventing misdiagnosis and optimizing treatment.

Ben Hunter, MD

Ben Hunter, MD

Anthony L Rostain, MD, MA

Anthony L Rostain, MD, MA

Premiere Date: July 20, 2018
Expiration Date: January 20, 2020

This activity offers CE credit for:
1. Physicians (CME)
2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.


To goal of this activity is to understand the sources of treatment-resistance in ADHD and how to ameliorate them by optimizing treatment.


At the end of this CE activity, participants should be able to:

• Identify the sources of treatment-resistant ADHD in adults

• Prevent misdiagnosis

• Optimize treatment


This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.


CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit ™.


It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations.

Ben Hunter, MD, has no conflicts to report.

Anthony L. Rostain, MD, MA, reports that he is a consultant to Shire, Ironshore, Arbor, Lundbeck, Major League Baseball, National Football Leagues, SUNY/Upstate.

Norman Sussman, MPA, MD, DFAPA (peer/content reviewer), has no conflicts to report.

Applicable Psychiatric Times staff and CME Outfitters staff, have no disclosures to report.


Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

Questions about this activity?
Call us at 877.CME.PROS (877.263.7767)

The prevalence of ADHD in adults is estimated to be 4.4% in the general population with ranges of 12% to 40% in patients with other psychiatric disorders, depending on the primary diagnosis.1,2 Increasing recognition of ADHD as a source of functional impairment in adults has meant that its treatment is moving from the domain of specialists into the office of general psychiatrists. This shift necessitates facility in the use of available pharmacologic and psychosocial treatments. But what happens when the initial treatment approach does not provide adequate results? Through discussion of three cases, in this article we identify sources of treatment resistance and provide suggestions for optimizing treatment.


John was a 19-year-old college freshman with a diagnosis of ADHD established in middle school who presented to the Penn ADHD Program with concerns that his stimulant medication was no longer working. He had been on the same daily dose of extended release mixed amphetamine salts (MAS) 20 mg in the morning along with 10 mg immediate release MAS in the afternoon since 11th grade, with generally good results until recently. John was enrolled in a very rigorous program in college that required him to read 250 to 300 pages of technical writing and to write up 2 lengthy lab reports and multiple homework assignments on a weekly basis. While he expressed a great deal of interest in his courses, it quickly became clear to him that the academic load was more than he had expected.

During his intake, John reported difficulty staying focused during lectures and lab sessions, often to the point that he would lose track of the course material. After class, John had trouble getting started on his assignments, often spending long periods of time internet surfing and chatting online with friends. He admitted that he had been spending excessive amounts of time socializing with his roommates and playing his favorite video games until late at night. He reported some continued benefit from the medication but noted that it was wearing off by the end of the morning instead of lasting through his afternoon classes and study sessions.

Despite recommendations for improving his scheduling and sleep hygiene plus an increase in MAS dosage to 20 mg of extended release twice daily, John continued to fall behind on his assignments and struggled to pass his courses. He had begun missing his morning classes because of his late-night gaming activities. When asked how the medication was working, he admitted to having increased his dose to 80 mg daily including a 20 mg dose at 8 PM. Much of the time, he was going to bed after 2 AM and not waking until after 10 AM, thereby missing many of his early morning classes.

Source of treatment resistance

Nonadherence and executive functioning difficulties

College students with ADHD face multiple challenges with respect to self-regulation, time management, and completion of complex academic tasks.3,4 The supportive “scaffolding” they were provided at home is no longer available in the college setting. Moreover, the perpetual distractions of social life and online activities make it difficult for college students like John to complete their assignments in a timely fashion. In response to his executive functioning challenges, John began overusing his stimulant medication partly out of the mistaken assumption that it would help him get organized and do his work more consistently, and partly out of a wish to extend his work day. Unfortunately, this strategy did not work because medication alone cannot overcome executive functioning deficits and unhelpful habits like procrastination and poor sleep hygiene. John was advised to make use of the college’s learning center services including tutoring and ADHD coaching.5

Key Point

• In the case of treatment resistance in college students, assess patient executive functioning, encourage utilization of learning center services and ADHD coaching, and investigate the possibility of medication misuse in order to enhance cognitive performance.

Clarifying diagnosis, changing area of study, managing expectations

John began taking advantage of college student support services and with the help of an ADHD coach, he began attending classes regularly, developed a more effective time management system, and was able to establish a healthier sleep-wake cycle. Despite these interventions, John remained overwhelmed with the high demands of his academic course of study. He was unable to maintain an adequate GPA to remain in the program and was asked to take an academic leave of absence. During his time away from school, he underwent psychoeducational testing and was found to have dyslexia and mild auditory processing difficulties. He was able to use this information to change his area of study and to receive academic accommodations when he returned to school. John took advantage of the school’s learning resources, developed better ways of getting started on his work in a timely fashion, and began to get better grades in his new major.

Key Point

• When patients exhibit learning and executive functioning difficulties, it is important to re-evaluate the underlying diagnosis and to encourage them to make professional decisions on the basis of new clinical information in order to optimize their likelihood for success and mastery.


Mary was 46 years old when she presented at an outpatient intake appointment. She reported longstanding difficulties with attention, task-completion, and organization. Looking back, she recalled these symptoms as early as grade school, describing herself as a “daydreamer” who would occasionally be punished by her teacher for lapses in attention. Through middle school and high school, she sensed that it took her significantly longer than her peers to complete assignments, particularly those requiring extensive reading, which often took multiple passes for Mary to comprehend. However, she was generally successful until college, when the course demands at a challenging private university overwhelmed her inefficient learning habits. Mary failed several liberal arts classes and dropped out after less than one year.

Mary met her husband soon after leaving college and became a homemaker. Despite a less strenuous cognitive workload, she continued to feel inefficient and disorganized. Mary described a daily routine of “flitting from one thing to the next” without actually completing any individual project, often forgetting to address multiple items within a given day if not explicitly recorded in a to-do list. After neuropsychological testing confirmed the results of scales completed by Mary and her husband, ADHD inattentive type was diagnosed, and Mary was started on methylphenidate ER.

Mary tolerated methylphenidate and was titrated to 36 mg with 50% improvement in symptom reports, but further titration was limited by “jitteriness.” Mary’s sense of despair was palpable on her subsequent visit. Her psychotherapist corroborated a theme of feeling fundamentally flawed and “broken,” more prominent over the past 3 to 4 weeks. Mary noted that she was having increasing difficulty starting tasks, and on several days over the past week, she had returned to bed after getting the children off to school.

Comorbid diagnoses

ADHD is highly comorbid, showing particularly strong associations with mood and anxiety disorders.1,6,7 Clinically, it is often difficult to differentiate between depression or anxiety causing executive dysfunction versus untreated ADHD causing disorders of mood and anxiety. In Mary’s case, it initially appeared that her past depressive symptoms had been secondary to the self-esteem issues and sense of unmet expectations that result from functional impairment as a result of poor attention modulation. However, with Mary’s stimulant dosed adequately and improvement in symptoms specific to the diagnosis of ADHD, the imperative became addressing residual depressive symptoms. Mary was started on sertraline and titrated to a dose of 150 mg, at which point she noted significant reduction in both her depressive and inattentive symptoms. Notably, Mary’s self-esteem, motivation, and ability to initiate tasks improved markedly.

Key Point

• Stimulants are highly effective in treating “uncomplicated” adult ADHD.8,9 In the case of treatment resistance, re-screen for comorbid medical or psychiatric disorders and treat underlying/comorbid disease optimally before making further adjustments to stimulants.

The “wearing off” effect

Despite a robust response to methylphenidate and sertraline, Mary continued to report difficulty falling asleep. She described herself as lying in bed with her “mind spinning,” an endless loop of repetitive thoughts and scenarios she felt unable to turn off. A review of Mary’s daily routine revealed that she typically dosed her stimulant around 6:30 AM, leading to the conclusion that its effects were likely wearing off in the early evening. Methylphenidate immediate release 5 mg was added at 4:00 PM with close monitoring to ensure this did not add to Mary’s sleep difficulties. As suspected, she reported a reduction of anxious inattentive thought processes around bedtime. The methylphenidate IR was titrated to 10 mg, and the dose was slowly moved back to 5:00 PM, at which point she was consistently able to fall asleep at her target time of 10:00 PM. With improved sleep on top of her established gains, Mary had remission of both ADHD and MDD symptoms.

Key Point

• If patients report difficulty falling asleep due to “racing thoughts,” “inability to shut down the mind,” or other similar complaints, consider extending dosing into the evening to cover reemerging inattentive symptoms driving insomnia. Stimulants have been demonstrated to positively affect architecture in the often-disrupted sleep of patients with ADHD.10



James was a 38-year-old consultant in the alternative energy industry transferring care from his primary care doctor, who felt unable to adequately treat James’s multiple psychiatric comorbidities. James’s history revealed ADHD, combined type, diagnosed and treated with multiple different classes and doses of medications beginning in elementary school. He was currently prescribed lisdexamfetamine (LDX) 40 mg daily with marginal reported improvement. In addition, James met criteria for persistent depressive disorder and generalized anxiety disorder with panic, stating that his current dose of fluoxetine 20 mg, started one month earlier, “did nothing.”

It was noted that James was boisterous and challenging during the interview. He openly expressed irritation at the psychiatrist’s refusal to add immediate release stimulants to his LDX without first optimizing long-acting therapy.


Unrealistic expectations of medications and/or physician

James made numerous phone calls between psychiatric appointments, requesting increased doses of stimulants in each case, clearly expressing anger that he would be required to schedule office visits for such changes. During these phone calls, he was encouraged to allow time for adequate trial of each dose and was reminded of the initial treatment agreement stating that doses would not be increased over the phone. James responded well to the established boundaries, and his demanding behavior ceased relatively quickly.

Through further discussion, it became clear that James was expecting more coverage than any regimen could reasonably achieve. A review of his dosing and daily activities revealed that he was attempting to work, or otherwise remain highly cognitively engaged, for 16 to 18 hours every day. James was disabused of this misguided treatment goal and reminded of the substantial benefits of healthy diet, exercise, sleep, and general self-care. A more modest expectation of 12 to 14 hours of daily coverage was set.

Key Point

• Inability to extend focus and concentration past normal human capacity is not treatment resistance. Early discussion of appropriate expectations for stimulant therapy, along with clear prescribing boundaries, are critical when treating challenging patients.


Despite improvements in his daily routine, James continued to demonstrate residual symptoms at the current dosage of stimulant. His LDX was titrated in 10 mg increments until he reached a dose of 100 mg (100 mg LDX is equivalent to 40 mg MAS delivered over 12 hours), which James felt was effective and resulted in demonstrably less irritability. James was examined closely for adverse effects at each dosage, and none were observed, including at the highest dose.

A commonly-observed phenomenon in patients referred to our clinic for treatment resistance is underdosing of stimulants. There is little evidence to corroborate the concern many clinicians feel in titrating these medications. As with antidepressants or other psychiatric medications, there is wide variation in the metabolism of these compounds and it is sometimes beneficial to exceed FDA dosing recommendations, ie, when the benefits of increased doses continue to outweigh adverse effects and health risks.11,12

Key Points

• Close monitoring is paramount when prescribing high doses of stimulants; check vital signs, consider an EKG, and screen closely for side effects.
• If not already attempted, a “class switch” (from amphetamine salts to methylphenidate, or vice versa) should be considered before moving to supra-FDA dosing.


Treatment resistance in adult ADHD can stem from several sources including treatment nonadherence, misdiagnosis, patient misconceptions, insufficient use of environmental restructuring and psychosocial interventions, and symptom persistence despite adequate treatment trials (bona fide resistance). Nonadherence in adult ADHD is extremely common and is linked to the symptoms of the disorder itself: namely, forgetfulness, disorganization, and difficulties with self-control. As it has been observed, the key problem facing adults with ADHD is “turning intentions into actions,” so even the most motivated patients often have trouble following through on medical instructions.13,14

Misdiagnosis often involves overlooking factors besides ADHD that may be impairing an individual’s ability to function. As the first case illustrates, hidden impairments like learning disabilities and auditory processing problems can significantly hinder academic success in college or graduate school. The second case exemplifies how comorbidities like depression and anxiety can interfere with optimal treatment. It is easy for clinicians to underestimate the extent to which patients’ distorted thinking about ADHD and its treatment can influence outcomes, as the third case illustrates. Providing ongoing psychoeducation and challenging unrealistic beliefs and expectations are the best ways to improve this situation. In a similar vein, emphasizing the importance of integrative care via environmental restructuring and psychosocial interventions (such as CBT and ADHD coaching) is another means to reduce treatment resistance. Increasingly, these approaches have been shown to add additional value to medical treatment for adult ADHD.15-17

It is important to remember that even with optimal treatment and adherence, a good deal of the impairment that results from ADHD is not effectively ameliorated. This stems in part from the underlying pathophysiology of the disorder which is both complex and yet poorly understood. Another mediator is the limitation of current interventions to repair the disordered brain processes that are constitutive of ADHD. As with many other neurodevelopmental disorders, treatment is primarily symptom-focused rather than curative. Despite these challenges, forging effective clinician-patient relationships, addressing expectations in a straightforward manner, fashioning a treatment plan with realistic goals, utilizing integrative methods, and maintaining a focus on promoting coping with the disorder are useful guides to intervention.



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