1. Pharmacologic Considerations in the Treatment of ADHD in Adults Presented by: Ann M. Wheeler, PharmD, BCPP Date: 3/31/2016

2. Disclosures and Learning Objectives Learning Objectives Be able to identify first-line treatment recommendations and treatment alternatives for adults with ADHD Disclosures: Dr. Ann Wheeler has nothing to disclose.

3. Pharmacologic Treatment of Adult ADHD Review Background information and clinical manifestations of adult ADHD Treatment alternatives Clinical pearls and treatment recommendations for stimulants and non-stimulants

4. Background Majority of people diagnosed with ADHD in childhood continue to meet criteria for the disorder as adults Associated with impairment in occupational, academic, and social functioning. Prevalence estimated to be 4.4% in the U.S. Characterized by symptoms of inattention, impulsivity, and restlessness, resulting in functional impairment.

5. Clinical Manifestations The predominant features of ADHD in adults differ from typical ADHD features in children. Symptoms of hyperactivity or impulsivity are less obvious in adults (impulsivity may be seen in verbalization rather than physical behavior) and symptoms of inattention are more prominent.

6. Clinical Manifestations Inattention: Problems remaining focused on a task, especially for long periods Difficulty in organizing activities, prioritizing tasks, following through and completing tasks, forgetfulness, and time management Adults with ADHD will often report that tasks are finished only at deadlines, often late or even not at all Increased problems related to driving, including increases in driving errors, traffic tickets, and speeding may be related to attention deficits

7. Clinical Manifestations Impulsivity: Characterized by excessive involvement in activities or speech that has a high potential for consequences Often results in more serious consequences than during childhood and may include premature termination of relationships or quitting jobs Impulsivity can also contribute to driving errors, traffic tickets and speeding

8. Clinical Manifestations Hyperactivity: Rather than overly hyperactive, adults with ADHD will seem or report feeling fidgety or restless. May report talking too much and/or interrupting others

9. Clinical Manifestations Executive Dysfunction: The following may be deficient in adults with ADHD Working memory Task-shifting Self-monitoring Initiation Self-inhibition These deficits contribute to the inattention problems characteristic of adult ADHD (e.g. remaining focused, organization, prioritization)

10. Clinical Manifestations Emotional Dysregulation: Mood lability, irritability, anger outburst, low frustration tolerance, and motivational deficits are commonly seen in adults with ADHD though not specific to the disorder.

11. Differential Diagnosis Depression ADHD shares with depressive disorders a diminished ability to think or concentrate, poor motivation to undertake activities, and indecisiveness. Depression can be distinguished from ADHD in adults by a typically later onset and episodic course. Mania ADHD shares with mania distractibility, impulsivity, and increased talkativeness. Mania can be distinguished from ADHD in adults by a typically later onset and episodic course.

12. Differential Diagnosis Anxiety Disorders ADHD is often accompanied by anxiety. Patients with anxiety disorders can be distracted by the focus of the disorder, which can present similarly to the distractibility seen in ADHD. In contrast to ADHD, distraction with an anxiety disorder only occurs in the presence of the focus of that disorder (e.g. preoccupied with a specific fear). The onset of anxiety disorders may be later than the onset of ADHD in adults. Substance Use Disorders Cognitive and behavioral impairments can be seen in both ADHD and in SUDs. Acute impairments in SUDs, however, occur only in the context of substance use.

13. Treatment Overview Short-term clinical trials of pharmacotherapy in adults with ADHD has shown efficacy in reducing ADHD symptoms and improving daily function. Evidence of long-term symptom reduction is largely from observational studies, which also suggest some benefit in functioning, including work performance, and in self-esteem.

14. Treatment Overview Stimulants Most extensively tested and commonly prescribed medications for ADHD across the lifespan. MOA in ADHD is unknown, but most likely involves increased intrasynaptic concentrations of dopamine and norepinephrine. Non-Stimulants Non-stimulant medications with efficacy in adult ADHD include atomoxetine, bupropion, and tricyclic antidepressants. Comparison of effect sizes in clinical trials suggests that stimulant medications are more efficacious.

15. Clinical Pearls—Stimulants There does not appear to be a substantial advantage in efficacy or side effects of preferentially using methylphenidate rather than amphetamine products, or vice versa. Choice of immediate or long-acting stimulant preparation is often dependent upon patient preference, cost, needed time of coverage, and/or concern about the potential for abuse/diversion (long-acting agents may be less prone to abuse/diversion)

16. Clinical Pearls—Stimulants Once a particular stimulant preparation is selected, it is started at low dose and titrated up at intervals ranging from weekly to monthly or longer. Because the attention symptoms characterizing adult ADHD are often subtle, more extended periods are often necessary to fully evaluate the effectiveness of each dose Titration continues until one of the following criteria are met: No room for improvement Intolerable adverse events Maximum dose limits

17. Clinical Pearls—Stimulants At each visit, prescribers should check: Report of positive and negative effects of the medication Duration of these effects following each dose Experience of non-therapeutic reinforcing effects (e.g. euphoria) If an inadequate response to one stimulant is seen, the patient can be switched immediately (no tapering/washout necessary) to another stimulant preparation

18. Adverse Effects Side effects of stimulants reported in adults treated for ADHD include: Dry mouth Insomnia Edginess/irritability Dysphoria Diminished appetite Weight loss Headache

19. Adverse Effects A meta-analysis of randomized trials found that 10% of adults with ADHD treated with stimulant medications discontinued the medication due to adverse events. Progressive titration to an optimally effective dose helps minimize side effects (use lowest dose possible)

20. Adverse Effects Other adverse effects: Psychosis: Has occurred with stimulant abuse and in treatment with stimulants in patients with a vulnerability to psychosis Cardiovascular effects: BP and HR should be monitored upon initiation and over the course of treatment. Consistent elevations in systolic and diastolic BP and HR have been found to result from stimulant use in adults. Research on the relationship between treatment and serious cardiac events has found mixed results: One population-based cohort study did not find an association between stimulant treatment and the risk of sudden CV events among young and middle-aged adults Another retrospective analysis found a 1.8-fold increase in sudden death or ventricular arrhythmia Priapism: Priapism is a rare complication of methylphenidate

21. Misuse and Abuse Amphetamine = Bennies, Black Beauties, Crosses, Hearts, LA Turnaround, Speed, Truck Drivers, Uppers Common ways taken: swallowed, snorted, smoked, injected Methylphenidate = JIF, MPH, R-ball, Skippy, The Smart Drug, Vitamin R Common ways taken: swallowed, snorted, smoked, injected, chewed National Institute on Drug Abuse: www.drugsabuse.govwww.drugsabuse.gov

22. Misuse and Abuse

23. Misuse and Abuse—CVS Survey Half of all the students surveyed in the CVS report said they took stimulants to assist with pulling an all-night study session or improving their academic performance. About 24% said they misused or abused these drugs to improve work performance at a job. 1 in 5 college students reported abusing prescription stimulants. About 56% of those surveyed said it’s easy to obtain prescription stimulants not intended for them. Among those who have a prescription, 52% said they had been pressured by friends into sharing or selling their medication Of the students with legitimate prescriptions, 28% admit to selling and/or sharing their pills

24. Non-Stimulants Atomoxetine Inhibits presynaptic norepinephrine reuptake, resulting in increased synaptic norepinephrine and dopamine Modestly more effective than placebo in reducing the core symptoms of adult ADHD Adverse effects: dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, erectile dysfunction, urinary hesitancy, dizziness, and sweating (discontinuation due to adverse effects compared to placebo = 17.2% vs. 5.6%)

25. Non-Stimulants Bupropion Antidepressant with mixed catecholaminergic effects Positive results have been found for both the QD (XL) and BID (SR) dosed preparations. Compared to placebo, bupropion led to a higher response rate and greater reduction in inattentive and overall ADHD symptoms in adult patients. Adverse effects: dry mouth, insomnia, nausea, dizziness, anxiety, dyspepsia, sinusitis, and tremor. May increase risk of seizures, particularly at higher doses and shorter-acting formulations.

26. Non-Stimulants TCAs Have demonstrated efficacy in adult ADHD Advantages: lack of abuse liability, single daily dosing, efficacy in co-occurring anxiety and depression Less effective and more poorly tolerated compared to stimulants, atomoxetine or bupropion Administration: Start at a low dose and titrate up slowly

27. Non-Stimulants Alpha-2 Agonists Little is known about the efficacy, safety and tolerability of alpha-2 adrenergic agonists clonidine and guanfacine in adults with ADHD Considered to be 4 th line following stimulants, atomoxetine and antidepressants

28. Other Medications Venlafaxine—may be mildly efficacious, only small studies SSRIs—only small studies, may be effective MOAIs—have shown mixed results, ADHD patients are likely poor candidates for this drug class Selegiline—no better than placebo Modafinil—little evidence of efficacy in adult ADHD Medication Augmentation—not currently supported by evidence in adult ADHD

29. Duration and Continuity When is the medication needed Vocational activities, educational activities or all activities Some may benefit or tolerate drug holidays (e.g. weekends) Some may require treatment for a limited time period, others may need them indefinitely

30. Treating ADHD in Co Occurring Disorders SUD Treatment of ADHD with a stimulant does not appear to affect the likelihood of subsequent SUD development Neither increasing SUD risk nor having a protective effect Clinical trials of stimulant treatment in ADHD patients with an active SUD have found mixed efficacy results, with only 1 of 4 trials showing a reduction in ADHD sx in the stimulant-treated group compared to placebo

31. Treating ADHD in Co Occurring Disorders Depression Bupropion and TCAs have demonstrated efficacy, with bupropion often better tolerated. Anxiety Combination stimulant and an SSRI are generally effective. TCAs provide a secondary alternative.

32. Treatment Selection Adults with ADHD Stimulants are generally first-line; non-stimulants are second- line ADHD and known h/o SUD Atomoxetine or bupropion is first-line Long-acting stimulants are second-line with careful monitoring for signs of misuse, diversion or addiction ADHD and active SUD Treat the SUD first prior to initiating pharmacotherapy for ADHD ADHD and depression Bupropion is first-line; Stimulant + an SSRI is an alternative ADHD and anxiety Stimulant + an SSRI

33. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Dexmethylphenidate Focalin and generic equivalents 0.5 - 1 hr5 – 6 hrs5 mg bid Inc total daily dose by 10 mg at weekly intervals 15 mg bid (maximum 20 mg bid) Focalin XR and generic equivalents 0.5 - 1 hr; a 2 nd peak occurs ~6.5 hrs p dose 12 hrs10 mg qd in AM Inc daily dose by 10 mg at weekly intervals 30 mg qam (maximum 40 mg qd)

34. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Methylphenidate—Shorting acting Ritalin and generic equivalents Methylin, chewable Methylin, oral solution < 1 hr; delayed if high fat meal 3 – 5 hrs10 mg bid before breakfast and lunch Inc total daily dose by 5 or 10 mg at weekly intervals 40 to 60 mg per day in 2 or 3 divided doses

35. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Methylphenidate—Intermediate acting Ritalin SR and generic equivalents < 1 hr4 – 8 hrs20 mg qd in AM Inc daily dose by 10 mg at weekly intervals 40 to 60 mg per day in AM Metadate ER and generic equivalents < 1 hr4 – 8 hrs10 mg bidInc daily dose by 10 mg at weekly intervals 40 to 60 mg per day in AM

36. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Methylphenidate—Long acting Metadate CD and generic equivalents < 1 hr; 2 nd peak occurs ~4.5 hrs p dose 8 – 12 hrs20 mg qd in AM Inc daily dose by 10 or 20 mg at weekly intervals 40 to 60 mg per day in AM Quillivant XR oral suspension < 1 hr8 – 12 hrs20 mg qd in AM Inc daily dose by 10 or 20 mg at weekly intervals 40 to 60 mg per day in AM

37. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Methylphenidate—Long acting Ritalin LA and generic equivalent < 1 hr; 2 nd peak occurs ~5.5 hrs p dose 8 – 12 hrs10 or 20 mg qd in AM Inc daily dose by 10 mg at weekly intervals 40 to 60 mg per day in AM Concerta and generic equivalents < 1 hr; plateau at 1 – 4 hrs and peak at 6 hrs p dose 10 – 12 hrs 18 or 36 mg qd in AM Inc daily dose by 18 mg at weekly intervals 54 to 72 mg per day in AM

38. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Methylphenidate—Long acting Daytrana transdermal patch < 2 hrs10 – 12 hrs 30 mg patch on for 9 hrs & off for 15 hrs each day Apply 2 hrs before needed onset Inc to next higher dose at weekly intervals; Available strengths: 10 mg, 15 mg, 20 mg, and 30 mg per 9 hrs 60 mg patch on for 9 hrs and off for 15 hrs each day

39. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Dextroamphetamine—Shorting acting Generics< 1 hr4 – 6 hrs5 mg bidInc total daily dose by 5 mg at weekly intervals 20 mg bid Dextroamphetamine—Long acting Dexedrine spansule and generic equivalents < 1 hr6 – 8 hrs5 mg bidInc total daily dose by 5 mg at weekly intervals 40 mg qd in AM

40. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Dextroamphetamine and Amphetamine (mixed salts)—Shorting acting Adderall and generic equivalents < 1 hr4 – 6 hrs5 mg qd or bid Inc total daily dose by 5 or 10 mg at weekly intervals 40 to 60 mg per day in 1 to 3 divided doses Dextroamphetamine and Amphetamine (mixed salts)—Long acting Adderall XR and generic equivalents < 1 hr8 – 10 hrs20 mg qd in AM Inc total daily dose by 10 mg at weekly intervals 40 to 60 mg qd in AM

41. Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Lisdexamfetamine Vyvanse< 1 hr; onset delayed if taken with food ~10 hrs30 mg qd in AM Inc total daily dose by 10 or 20 mg at weekly intervals 30 to 70 mg qd in AM

42. Non-Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Atomoxetine Strattera1 to 2 weeks 24 hrs40mg qdInc after 3 or more days to 80 mg; after 2 to 4 weeks may increase to 100 mg per day 80 mg qd or in two equally divided doses (maximum 100 mg per day)

43. Non-Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Clonidine extended-release Kapvay1 to 2 weeks 12 hrs0.1 mg qd at bedtime Inc daily dose by 0.1 mg at weekly intervals 0.1 to 0.3 mg qd or in two divided doses (maximum 0.4 mg/day) Guanfacine extended-release Intuniv1 to 2 weeks 8 to 14 hrs 1 mg qdInc daily dose by 1 mg at weekly intervals 1 to 4 mg qd

44. Non-Stimulants MedicationOnset of Initial Effect Duration of Effect Initial Dose TitrationMaintenance Dose Bupropion Wellbutrin SR or generic equivalents 1 to 2 weeks 12 hrs150 mg qd in AM After 3 days increase to 150 mg bid 150 mg bid (maximum 200mg bid) Wellbutrin XL or generic equivalents 1 to 2 weeks 24 hrs150 mg qd in AM After 3 days increase to 300 mg qd 300 mg qd (maximum 450 mg qd)

45. The End Next Week: TBD