References

1. Franke B, Neale BM, and Faraone SV. Genome-wide association studies in ADHD. Hum Genet 2009; 126(1): 13–502. Haberstick BC, Timberlake D, Hopfer CJ et al. Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder. Psychol Med 2008; 38(7): 1057–663. McLoughlin G, Ronald A, Kuntsi J et al. Genetic support for the dual nature of attention deficit hyperactivity disorder: substantial genetic overlap between the inattentive and hyperactive-impulsive components. J Abnorm Child Psychol 2007; 35(6): 999–10084. Todd RD, Rasmussen ER, Neuman RJ et al. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am J Psychiatry 2001; 158(11): 1891–85. Faraone SV, Advances in the genetics and neurobiology of attention deficit hyperactivity disorder, Biol Psychiatry 2006; 60: 1025–76. Stahl SM, Stahl’s Illustrated Attention Deficit Hyperactivity Disorder, Cambridge University Press, New York, 20097. Stahl SM, Attention Deficit Hyperactivity Disorder and its Treatment, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 863–988. Stahl SM, Lisdexamfetamine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 271–69. Stahl SM, Atomoxetine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 51–510. Stahl SM, Guanfacine XR, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 233–511. Stahl SM, d-Methylphenidate, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 323–712. Stahl SM, d,l Methylphenidate, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 329–3513. Stahl SM, Mixed Salts of d,l amphetamine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 39–4414. Stahl SM, d-amphetamine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 33–8

Patient FileThe Case: The scatter-brained mother whose daughter has ADHD, like mother, like daughter

The Question: How often does ADHD run in families?

The Dilemma: When you see a child with ADHD should you also evaluate the parents and siblings?

Pretest Self Assessment Question(answer at the end of the case) Patients with comorbid ADHD and anxiety should in general not be prescribed stimulants

A. True

B. False

Patient Intake 26-year-old woman

Has a daughter with ADHD

Psychiatrist noted symptoms in the mother and suggested she come in for her own evaluation

See the previous Case 13, p 133 for presentation of the daughter’s case

Psychiatric History During interviews with the patient’s daughter (also attended by the patient) over the past several months, it was not only noted that the daughter has ADHD with comorbid ODD, but that the mother also exhibited multiple symptoms consistent with lifelong and undiagnosed ADHD including– Mother misses appointments or is late for appointments– Often appears disorganized– Did not fill out her child’s forms on time– Did not deliver forms to her child’s teacher, forgot, lost them– Admits being very disorganized since her second child started school– Feels overwhelmed by two children and her life circumstances– Could also have some signs of depression– Can’t get organized to take her child to CBT– Has a hard time keeping a regular schedule and also keeping her daughter on a regular schedule of going to bed and waking up– Was unable to remember to remove the daughter’s skin patch unless she set a cell phone alarm– All these suggest further evaluation of the mother is indicated since ADHD commonly runs in families and has a very high genetic contribution

Has always done poorly academically

Has always felt intimidated by any type of testing

In addition, reports that she has always been worried about the future and financial stability of her family

Says she sometimes mentally “freezes when it gets to be too much”

When her eight year old daughter was diagnosed with ADHD, she suddenly realized that she had similar problems as a child

The psychiatrist explained to her that ADHD was highly heritable and that there was a 75% chance of having a child with ADHD if both parents have ADHD and thus was asked to fill out an Adult ADHD screening form

Social and Personal History High school drop out, age 17 after getting pregnant

Married age 17, divorced 2 years later

Two children, ages 8 and 6

Smoker

No drug or alcohol abuse

Single mother works full time in retail

Father not much involved with his children

Medical History None notable

BP normal

BMI normal

Normal lab tests

Family History 8-year-old daughter: recently diagnosed with ADHD

Other family history unknown as the patient was adopted

See the previous Case 13, p 133 for presentation of the daughter’s case

Patient Intake The last time the patient brought her child to see the psychiatrist, the mother was asked to fill out her own checklist, the Adult ADHD Self Report Scale Symptom Checklist– She endorsed many items, mostly inattentive but not really hyperactive or impulsive such as:– Having trouble wrapping up the final details of a project once the challenging parts have been done– Difficulty getting things in order– Difficulty remembering appointments or obligations– Making careless mistakes on difficult projects– Difficulty keeping attention on repetitive work– Misplacing things at home and work– Distracted by activity around her– Difficulty unwinding and relaxing when having time to herself– Difficulty focusing/listening during conversations

Earlier, the mother was also requested to obtain copies of her report cards from first and second grade– Her own mother had kept these in storage– Showed grades that were quite low– Her teachers had commented on some of the problems endorsed in the adult ADHD checklist that she continues to experience as an adult

Asked how these problems affect her life, she states that:– They cause great difficulty managing family matters– She used to be unable to stay focused in conversations with her ex-husband, which made him feel she did not care about him

Additional complaints include:– Constantly feeling overwhelmed with taking care of the two children while working fulltime– Blaming herself for her daughter’s academic difficulties– Feeling very emotional and overwhelmed– “I’m sorry, doctor, but two kids are just too much for this single mom”

Having difficulty sleeping and being irritable with the children at night, which she regrets later on

Has many worries, about finances, about the future, about her children’s futures, about getting a better job, about getting her own education, about finding a new partner

Based on just what you have been told so far about this patient’s history and symptoms, what do you think is her diagnosis?

Appropriate response to her circumstances with her severe psychosocial stressors

Mostly just stress and anxiety

ADHD

ADHD and stress

Generalized anxiety disorder (GAD)

Major depressive episode

ADHD and GAD

Other

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Here is a case that indeed is ADHD, but her symptoms also suggest that she suffers from GAD– Constant worry– Feeling on edge– Fatigue– Difficulty concentrating and her mind going blank– Irritability– Trouble sleeping

Most adults with ADHD are comorbid for a second psychiatric disorder, and the most common is GAD

Also, this patient is a smoker which may be related to her ADHD since a disproportionate number of ADHD patients smoke, perhaps because of the therapeutic effects of nicotine on ADHD symptoms

How would you treat her?

Stimulant for her ADHD

SSRI/SNRI for her GAD

Benzodiazepine as need for GAD and insomnia

Stimulant plus an SSRI/SNRI or benzo for both ADHD and GAD

CBT for both ADHD and GAD

Other

Attending Physician’s Mental Notes, Initial Psychiatric Evaluation, Continued It seems as though the primary disorder is ADHD and it will be simplest if this is treated first, with a single drug, probably a stimulant

An SSRI/SNRI and/or benzodiazepine can be added at a later time once the actions of the stimulant are evident

Even though patients with GAD alone or even normal controls may be “over stimulated” by a stimulant, in many cases of ADHD comorbid with GAD, the stimulant is paradoxically calming and well tolerated and even works for GAD symptoms as well as ADHD symptoms without having to prescribe a second medication for the GAD

Any stimulant could be chosen but not all are explicitly approved for treatment of ADHD in adults

She was started on mixed salts d,l amphetamine XR (Adderall XR)

She was referred to a local mental health training program where she could possibly get CBT for free or for a reduced rate from a trainee receiving supervision

Case Outcome: First, Second, and Third Interim Followup Visits, Weeks 4, 8 and 12 Due to scheduling issues, by the time the patient had her first CBT session, she had already been titrated to 20 mg of mixed salts of d,l – amphetamine XR

She thought that the medication had already started to help her and in fact that she would not have been able to cooperate with the CBT assignments had she not been on the medication

Because of lack of side effects but continuing ADHD and GAD symptoms, the dose of d,l-amphetamine XR increased to 30 mg (off label since the maximum approved dosage for adults is 20 mg)

Her BP and pulse were stable on the 30 mg dose but she felt jittery particularly in the morning and around noon; she also felt very anxious about her job situation and being able to provide for her family

Dose lowered to 25 mg, but the jitteriness persisted so the dosage was further lowerd to 20 mg

The jitteriness abated but her ADHD symptoms were not well controlled on the 20 mg dose anymore

Instructed to stay on 20 mg for two more weeks as she is going on vacation and not to change the dose until after her vacation and then retry the 25 mg dose again

Complained of feeling overwhelmed and irritable

For most patients, a week between dosing adjustments for a stimulant being used to treat ADHD is quite adequate

Weekly intervals give patients and clinicians a chance to see the way that the dosage is working though the spectrum of challenges that occur in a typical week

As vacations do not represent typical activities for a week, special consideration must be given to the effectiveness of medication changes that are done while a patient is on vacation– Many adults with ADHD may relax on vacation and not challenge themselves with cognitive loads and multitasking so may appear to be better even without a medication change– Other adults with ADHD, especially women with young children, may actually find vacation more challenging– For example, a parent with ADHD taking a family vacation with several children in tow may find the planning and organization for the trip more taxing than anything encountered at work or during the normal routine at home– It can also be difficult to manage timing the medication appropriately when traveling to different time zones

Case Outcome: Fourth Interim Followup, Week 16 “Glad to be back from vacation”

“I don’t think I could have even got through our vacation without my medication, but I still have a hard time holding things together”

On at least 20 mg/day dosage of d,l-amphetamine XR combined with CBT for 12 weeks, including a couple of weeks back from vacation, the patient still has problems with– Organizing her day– Procrastinating– Following instructions– Losing items such as her keys which make her late for appointments/activities

On the few days that the patient missed, and thus skipped, her medication inadvertently she realized that the medication was really helping her concentrate and get through the day even though she remains symptomatic

Knowing that she could achieve better functioning on medication she asked if other medications might accomplish this without the jittery and anxious feelings

While other medication options were discussed, the CBT was continued which was slightly less helpful

How would you treat her now?

Start lisdexamfetamine 30 mg once in the morning and titrate the dosage by 20 mg each week until an optimal dosage is achieved

Start d-methylphenidate XR 10 mg once in the morning and titrate the dosage by 10 mg each week until an optimal dosage is achieved

Start OROS methylphenidate 18 mg once in the morning and titrate the dosage by 18 mg each week until an optimal dose is achieved

Start atomoxetine 40 mg a day and increase to 80 mg after one week

Attending Physician’s Mental Notes: Fourth Interim Followup, Week 16 Lisdexamfetamine, d-methylphenidate XR, OROS methylphenidate, and atomoxetine are all FDA-approved for the treatment of adults with ADHD

On the one hand, the patient found her amphetamine-based stimulant to be very effective, and thus another long-acting stimulant would be reasonable

On the other hand, she had jitteriness with the stimulant, and thus a non-stimulant would be equally reasonable

After explaining the options, the patient elected to try another long-acting stimulant

d-methylphenidate uses a bead-based technology similar to the mixed salts amphetamine XR in that 50 percent of the beads are immediate-release and 50 percent delayed-released

Methylphenidate LA and d-methylphenidate XR employ the same patented SODAS technology in their delivery systems, but other long-acting forms of stimulants with beaded delivery systems vary due to proprietary differences in their manufacturing processes

For instance, one formulation of methylphenidate utilizes a capsule that contains a ratio of 30 percent immediate-release beads and 70 percent delayed-released beads

Although the different technologies used in beaded forms of stimulants can have clinical implications in individual cases, they all follow a similar design scheme:– A bolus of stimulant medication becomes bioavailable rather quickly as the immediate-release beads dissolve– Over time, the coating on the delayed-release beads deteriorates, allowing the stimulant contained within the bead to be released– The medication within the delayed-release bead becomes bioavailable about four hours after the patient swallows the capsule

Lisdexamfetamine is the only stimulant preparation that is a prodrug:– In its prodrug form, a lysine molecule is attached to dextroamphetamine– Dextroamphetamine will not be active until the lysine is cleaved from it– Cleaved lysine is an amino acid that does not contribute to the clinical efficacy of this medication

Lisdexamfetamine could be a good choice for multiple reasons:– It uses a different delivery system that appears to have a more consistent interval to maximum concentration (Cmax)

It is conceivable that the jitteriness this patient was experiencing was related more to the l-isomer than to the d-isomer

A nonstimulant such as atomoxetine may be particularly useful in a patient who has stimulant related side effects, because atomoxetine does not cause these side effects

Also, atomoxetine may be particularly useful in patients with comorbid anxiety

Case Outcome: Fourth Interim Followup, Week 16, Continued In the end, the patient and the attending physician agreed upon a trial of OROS methylphenidate (Concerta)

Main reasons for this choice:– To be able to compare the benefits the patient experienced on an amphetamine preparation with those of a methylphenidate preparation since patients may experience differing tolerabilities as well as efficacies on methylphenidate versus amphetamine– To be able to test the uniqueness of the OROS delivery system in terms of attained efficacy with better tolerability

OROS methylphenidate uses a delivery system that is quite different from beaded delivery systems:– Coating of OROS methylphenidate contains 32 percent of the medication– Remainder of medication is contained within a permeable membrane that allows water from the gut to enter once the coating of methylphenidate dissolves away– Different concentrations of methylphenidate in gel form are contained in two compartments– A push compartment absorbs water and expands like a sponge does, pushing the methylphenidate gel out of the hole at the opposite end

Case Outcome: Fifth Interim Followup, Week 20 The patient’s dose was titrated from 18 mg to 72 mg over the course of four weeks

Although she did not feel jittery, OROS methylphenidate 72 mg once a day did not seem to work as well as the mixed salts amphetamine at 30 mg a day

She voiced concerns that the dosage was more than double that of the mixed salts amphetamine dosage that was tried

The psychiatrist explained that methylphenidate compounds are half as potent as amphetamine ones, and that 72 mg/day is an approved dose in adults

She was reminded that her blood pressure and pulse had remained in the normal range throughout the titration, and she was told that some of the methylphenidate gel may remain inside the delivery system and not be bioavailable (inherent properties of OROS technology)

After documenting that information about off-label use was given to the patient, the psychiatrist recommended to further increase the dose of OROS methylphenidate to 90 mg

Case Outcome: Sixth Interim Followup, Week 24 The patient felt that 90 mg of OROS methylphenidate worked at least as well as 30 mg of the mixed salts of d,l amphetamine XR

Her blood pressure and pulse increased a bit from baseline, but they were still in the middle of the normal range

She still has some problems with organization and losing items, but she indicates she would continue CBT to address these

Similar to when she was on the amphetamine compound, once her ADHD symptoms abated, her anxious feelings became more prominent– “It’s like now that I can concentrate on my daily tasks, I also feel much more anxious about the financial security of my children, and I often feel my throat tighten when I think about the financial impact of the girls going to college”– “The thought of losing my job or getting sick frightens me … what would happen to the girls?”– She has trouble falling asleep at night, as her mind does not shut off

ADHD is often comorbid with other psychiatric disorders and one disorder can mask the symptoms of another. In the present case, this patient exhibits symptoms of anxiety, probably generalized anxiety disorder, especially more prominent every time her ADHD symptoms abate. How would you address the patient’s anxiety at this point?

Augment with a benzodiazepine

Augment with buspirone

Augment with a selective serotonin reuptake inhibitor (SSRI) or SNRI

Incorporate techniques to resolve anxiety into ongoing CBT

Case Outcome: Seventh and Eighth Interim Followup, Weeks 24 and 36 Incorporating techniques to resolve anxiety into the patient’s ongoing CBT would likely be most appropriate, prior to attempting to add a medication

A letter was sent suggesting this to the CBT therapist, but after 12 weeks, this led to limited benefit, and thus medication augmentation was considered

Benzodiazepines, buspirone, and SSRIs/SNRIs can all be used to treat generalized anxiety disorder and are not contraindicated with stimulants

After discussion of the options, paroxetine was prescribed to augment her stimulant and her CTB

Case Outcome: Ninth Interim Followup, Week 48 After three months on OROS methylphenidate and paroxetine, while continuing her CBT, at first the patient stated that she “had her life back”

Then, after thinking back over the past year of treatment, and to how she had been since childhood she stated, “No, I don’t have my life back – I finally have a life!”

Case Debrief It took a long time to get both the ADHD and GAD recognized

It took over a year of trial and error and combination treatment to attain a remission of symptoms

Real remission will come when sustained improvement of symptoms leads to better functional outcomes, not only less subjective distress, but now perhaps the chance for an education, a better job, and having enough emotional reserve to develop another relationship

Stopping smoking might be a goal to tackle in the next year as well

Take-Home Points ADHD is highly heritable

It is not uncommon for adults with previously undiagnosed ADHD to recognize their own symptoms once their child is diagnosed

A multigenerational approach should be considered for parents who have ADHD and who care for children with ADHD

In the patient’s case, by addressing her own ADHD issues, she also felt she could be a better parent to her daughter with ADHD

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Perhaps ADHD could have been recognized earlier– Perhaps CBT could have been implemented earlier– Perhaps she should have been more actively engaged or have had more serious discussions about smoking cessation already

Possible action item for improvement in practice– Make a concerted effort to keep contact with low cost CBT resources in the community– Make a more concerted effort to encourage smoking cessation

Tips and Pearls Prescribing stimulants to an ADHD patient is very much like tailoring a “bespoke” treatment, one case at a time

That is, some patients respond very differently to amphetamine than they do to methylphenidate

Many patients respond very differently to one controlled dosage pattern versus another

Look for comorbidities in adult ADHD, including both anxiety disorders and substance dependence/abuse (especially smoking)

True remission means reduction not just in symptoms of ADHD, but in the comorbid conditions as well

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – ADHD rating scales for adults

– Contributions of genetics to ADHD

Table 1: Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist Instructions Figure 1: Average Genetic Contribution of ADHD Based on Twin Studies ADHD is one of the most genetically loaded medical or psychiatric conditions, higher than schizophrenia, asthma or breast cancer.

Posttest Self Assessment Question: Answer Patients with comorbid ADHD and anxiety should in general not be prescribed stimulants

A True

B False

Answer: B