Advances in ADHD Management: Maximizing Effects While Minimizing Side Effects of Treatment
Release Date: November 14, 2008; Valid for credit through November 14, 2009
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Physicians - maximum of 1.5 AMA PRA Category 1 Credit(s)™ for physicians
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To participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation; (4) view/print certificate View details.
Contents of This CME Activity
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A Young Father on the Brink of Divorce |
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Case PresentationJason is a 29-year-old married man with 2 small children who works at his father-in-law's hardware store. He presented to a psychiatrist at the insistence of his wife. Jason reported, "I feel nervous all the time, always on guard. I'm having trouble at work and my supervisor complains because I am frequently absent. I have even bigger problems at home. I'm not getting anything done and my wife is so frustrated with me. I'm impatient with my children and she says that I yell at everyone in the house. She's talking about divorcing me." The psychiatric interview revealed that Jason has a long history of anxiety. As a child he missed a good deal of school because of separation anxiety. He was an average student but was frustrated that over the past 7 years he had been unable to complete an Associate's degree at the community college. During his teens Jason abused alcohol, but since getting married he had remained sober. The psychiatrist learned that the last few years have been punctuated by marital conflict. Much of the tension was related to Jason's inability to sustain gainful employment. In the past 7 years he had lost 5 jobs. As an adult, he had resisted seeking mental healthcare until 9 months ago, when his internist diagnosed him with depression and implored Jason to begin a serotonin reuptake inhibitor (SRI). On this medication, Jason's symptoms persisted unabated and a serotonin norepinephrine reuptake inhibitor (SNRI) was substituted. Frustrated with Jason's lack of progress with the second antidepressant, the primary care physician referred him to the psychiatrist. After the intake interview, the psychiatrist asked Jason to complete several screening tools. The Hamilton Depression Scale[1] was moderately elevated as was the Hamilton Anxiety Scale.[2] A substance-abuse scale revealed no active use, although it captured Jason's fear of relapse. Notably, the Adult ADHD Self Report (ASRS)[3] was strongly positive. Suspecting that Jason's history, symptoms, and impairments were consistent with adult attention-deficit/hyperactivity disorder (ADHD), Jason and his wife were given an educational video detailing the adult ADHD experience. The DVD was narrated by patients who had been treated successfully. At the next visit, Jason's wife reported that the video had accurately described her husband's struggles. After a lengthy discussion about treatment and with his wife's strong urging, Jason hesitantly accepted a prescription for a long-acting amphetamine. Counseling was also arranged. Beginning TreatmentThe following day, the doctor's office received a fax from Jason's managed care organization indicating that the long-acting stimulant would not be approved. Policy demanded that generics be prescribed and the psychiatrist, having no option, rewrote the prescription for short-acting methylphenidate 3 times daily. At the return visit, Jason reported that he was content attending counseling. Upon questioning, Jason conceded that he took very few tablets of his short-acting methylphenidate. As the doctor inquired, Jason reported a slew of other concerns. He had recently read that ADHD was overdiagnosed, and because he was not hyperactive as a child, he questioned the validity of the diagnosis. He was concerned that ADHD medications would elevate his blood pressure and resurrect his addictive behavior. Finally, he complained that he was unable to sustain the thrice-daily methylphenidate schedule. With the prompting of his wife and doctor, Jason agreed to try the long-acting amphetamine taken daily each morning. Soon thereafter, his wife emailed the psychiatrist, proclaiming an excellent response. On treatment Jason was more energetic, productive, and punctual. His job performance and attention to his family's needs improved. Her enthusiasm was tempered by her husband's persistent complaints about side effects. At his next visit, Jason reported some functional gains, but complained of poor appetite, insomnia, and some agitation. DiscussionEffective management involves addressing Jason's resistances as well as a proper response to medication side effects. Only by acknowledging both avenues can treatment optimization occur. Three Common Myths About ADHDPatients entering treatment for ADHD have myriad concerns and expectations. When told by a physician that the diagnosis is ADHD, patients often display initial resistance. The treating physician is likely to encounter recurrent assumptions that he or she should be prepared to address, such as the following: 1. ADHD is not a legitimate medical condition. ADHD is real and is characterized by patterns of inattention, hyperactivity, and impulsivity that are disproportionate to others and cause functional impairment in multiple settings. Although the origins of the condition are unknown, the consensus is that the disorder may be caused by an imbalance of dopamine and norepinephrine. Manipulation of these 2 neurotransmitters is the fundamental target of current pharmacologic treatment. The fact that the condition runs in families fortifies the argument that ADHD is biologically based and genetically transmitted. 2. ADHD is a disorder of children. One of the most important realizations in the field over the past 20 years is the finding that the condition persists into adulthood. A recent meta-analysis[4] found that up to 65% of children with ADHD exhibit symptoms into adulthood. The most cited prevalence study asserts that 4.4% of American adults meet diagnostic criteria. ADHD in adults presents differently. As an example, hyperactivity diminishes with age but inattention persists.[5] Jason's long history of generalized anxiety is consistent with, but not diagnostic of, childhood ADHD. 3. Even if I have the condition, the impact is minimal. Recent longitudinal data prove otherwise. Joseph Biederman, MD, and colleagues[6] at Massachusetts General Hospital followed patients with ADHD over time and found that adults with the condition were significantly more likely than their non-ADHD peers to have been divorced or separated, arrested, addicted to tobacco, used alcohol excessively, and experienced multiple motor violations in 1 year. The adults with ADHD in this study were also less likely than their non-ADHD peers to report "fitting in" well with their peers and having good relationships with their parents. Similarly, Russell Barkley, PhD, and colleagues[7] conducted a longitudinal study that followed a sample of individuals with ADHD and a community control group for 20 years. They found that compared with the control group, ADHD adults fared poorly. They had a higher percentage of problems with sleep, social relationships, family interactions, tobacco use, nonmedical drug use, medical/dental care, motor vehicle safety, work and leisure, and emotional health. These 2 pivotal longitudinal studies reinforce the heavy burden associated with the condition. Medication Management of ADHD / Selecting the Appropriate AgentMedications are paramount to effective ADHD management. Jason's outcome is largely a function of the refinement of his medication regimen. Stimulants are the hallmark of ADHD treatment, and optimal management requires a nuanced approach. As seen with Jason, certain issues predictably arise in clinical practice. Short-acting vs Long-acting MedicationsIn recent years, ADHD medications have been made available in long-acting preparations. Long-acting preparations are less likely to be diverted[8] and this enhances physician prescribing confidence. A 2006 study found that 1 out of 5 adolescents with ADHD had misused their drugs. Of the abusing group, 80% crushed or melted short-acting stimulants so that they could be snorted or injected.[9] In an adult study, Kollins[10] further demonstrated that short-acting agents yielded significantly greater drug "likeability," a finding that underscores a higher propensity for misuse. Research and clinical consensus support several reasons to avoid short-acting medications. Spencer and colleagues[11] reported that osmotic controlled-release oral delivery system (OROS) methylphenidate (90 mg) was absorbed more evenly than an equivalent amount of short-acting methylphenidate. Multiple daily doses are less convenient and are associated with diminished adherence. Furthermore, rapid blood level fluctuations make their clinical effects difficult to assess. For all of these reasons, including the fact that none these agents has received US Food and Drug Administration (FDA) indication for treatment of ADHD in adults, managed-care pressures to use short-acting agents should be resisted. Initial Dosing StrategiesFive medications recently have been approved for the treatment of ADHD in adults, and each has different properties. See Table for dosing guidelines. Table. Initial Dosing, Daily Dosing, and Booster Medications for FDA-Approved ADHD Agents (specifically approved for adults)
*Per FDA label recommendations. Doses may be higher in actual practice. Initial dosing strategies are crucial; if the patient receives an insufficient amount of medication with no clinical benefit, he or she might prematurely abandon treatment. Similarly, medication regimens that are initially too aggressive may cause intolerable side effects and have the same negative result. Close monitoring is vital. The physician should be available through phone calls or email and the patient should be seen for follow-up within 2-4 weeks of commencing treatment. For the first several months of treatment, assess the patient regularly and prepare to adjust the dosage. At regular visits, the patient should be queried about his clinical response. He should be asked about how he is feeling and functioning. Optimal dosing can be reached using both the patient's subjective response and objective data obtained through serial rating scales. Dosing should be titrated to the point of diminished returns or the emergence of side effects using the maximum dose parameters as a general guide. Baseline Symptoms vs Side EffectsPhysicians who treat the adult with ADHD must assess the baseline physical and psychological symptoms before beginning medication treatment, as some of the medication side effects are difficult to distinguish from underlying ADHD symptoms themselves. A discussion of sleep disturbances in the adult ADHD patient illustrates the confounding nature of this process. Insomnia and Sleep ArchitecturePreexisting sleep issues. A recent German study by Sobanski and colleagues[12] found that adults with ADHD, compared with a non-ADHD control group, displayed altered sleep architecture. Using sleep electroencephalography, Philipsen and colleagues[13] verified the absence of findings other than noting increased nocturnal activity. Studies based on parental reports have shown that sleep problems are significantly more prevalent in children with ADHD compared with their non-ADHD peers in control groups.[14] These complaints persist into adulthood. Thus it is important to obtain a baseline assessment of sleep instead of reflexively implicating the patient's ADHD medication. The physician should consider the possibility that a patient's sleep disturbances may result from underlying ADHD symptoms or comorbid restless legs syndrome, obstructive sleep apnea, or some other primary sleep disturbance. Sleep disturbance as a side effect. Most of the ADHD medications are associated with sleep difficulties. Of patients taking lisdexamfetamine, 19% reported insomnia as an adverse event[15] compared with 12.3% of adults taking OROS methylphenidate , although in both studies only a small percentage of subjects discontinued use because of this adverse event.[16] The clinical benefit of long-acting agents rarely exceeds 9-13 hours, but if sleep complaints arise, the patient should be instructed to take the stimulant as early as possible to ensure that it has been metabolized by bedtime. If this is unhelpful, consideration of a shorter-acting agent is reasonable. Stimulant-related insomnia is often transient. In persistent situations, non-benzodiazepine hypnotics may be employed to advantage. Impact of pharmacologic ADHD treatment on sleep. Untreated ADHD is associated with sleep disturbances as are many of the common medications used for treating ADHD. It appears counterintuitive that pharmacologic treatment of these symptoms can also aid in improving sleep for the adult with ADHD. In these patients, insomnia may be a result of the ADHD, not a side effect of treatment. These patients report that it is difficult to "turn their brains off" when it is time to sleep. Young[17] describes sleeplessness as a nighttime manifestation of the "racing thoughts" that these patients experience during the day. Dodson[18] reports successful use of evening-administered mixed amphetamine salts for the treatment of insomnia. This observation is fortified in a study of the impact of methylphenidate on the sleep architecture in adults with ADHD. Sobanski[12] found that the study participants, when treated with methylphenidate, experienced statistically significant improvements in sleep. Sleep hygiene promotion. Clearly, ADHD and sleep disturbances are associated, and this association may differ from one individual to the next. Regardless of the circumstance, physicians should promote proper sleep hygiene techniques, including avoiding caffeine within 4 hours of bedtime, taking a hot bath or shower before bed, drinking warm milk or chamomile tea, and trying to avoid taking any medications that may interfere with sleep before bedtime.[19] At low doses, mirtazapine, a tetracyclic antidepressant, has been employed in this population to induce sleep and elevate mood.[20] Substance AbuseOne of the more serious ramifications of untreated ADHD is the risk for substance abuse in these untreated individuals. The National Comorbidity Replication reported that 15.2% of adults with ADHD have a substance-use disorder, as compared with 5.6% of their non-ADHD peers.[21] Treating the individual with ADHD who has a history of substance abuse is a controversial topic. Some physicians are reluctant to use medications to treat these individuals. In a meta-analysis of available studies, Faraone and Wilens[22] found a 1.9-fold reduction in substance-abuse risk in ADHD adolescents treated pharmacologically as compared with their ADHD peers who did not receive treatment. With this finding, others have concluded that successful pharmacologic treatment provides adequate symptom relief, making this population less likely to self-medicate. Other Common Side Effects of ADHD MedicationsDyspepsia and anorexia. Most ADHD medications are associated with gastrointestinal complaints, particularly changes in appetite (often leading to weight loss) and stomachaches.[23] The patient should be informed that these are usually mild and transient. In clinical studies and everyday practice, these adverse events rarely result in the need to discontinue the medication. Management of dyspepsia involves slowing down the rate of titration until the symptoms dissipate or the patient accommodates. Encouraging the patient to eat a small amount of food before taking the morning dose is advisable, particularly for atomoxetine. Anorexia is also frequently reported. Usually mild, this symptom tends to be more persistent than the dyspepsia. Most adults welcome this development, although tall, thin young men, a group least in need of weight loss, are sometimes the most susceptible. Clinical management involves informing the patient that the anorexia is usually short-lived. If anorexia continues, patients should be instructed to "graze" -- that is, to eat small, frequent meals. The clinician should be aware of this potential side effect and that a small group of individuals seek stimulants specifically for this anorectic property. Research into pharmacologic interventions to combat stimulant-induced anorexia has not been pursued aggressively. Dry mouth. For most patients, medication-induced dry mouth is more of an inconvenience than a serious concern. Most counteract the symptom by chewing gum or hard candies and drinking bottled water. Still, some patients report that these techniques are not effective. Over time, they note halitosis and an higher incidence of dental cavities. Switching to a long-acting agent of another class may prove helpful. Chronic stimulant use and the resulting dry mouth can lead to the development of lip pursing, ostensibly an attempt to draw out more saliva. This can cause painful mouth ulcers. In these extreme cases, treatment with cevimeline hydrochloride, a medication approved to treat dry mouth for patients with Sjogren's syndrome,[24] offers relief when prescribed up to 3 times daily. Treatment of this side effect often allows the patient continued use of the stimulant. Stimulant-induced agitation/end of dose effect. ADHD patients treated with stimulant medications may report that they become short-tempered. Some observe that the medications cause hyperfocus and that outside distractions (ie, children making noise or a coworker's demands) agitate the individual, resulting in an outburst. The proper approach to this complaint is to lower the dose or switch to another agent. Some physicians associate this problem more often with amphetamines than methylphenidates. It is important to distinguish stimulant-induced agitation -- which occurs during the dose effect -- from an end-of-dose effect. In this situation, a careful history reveals that the patient feels and functions well most of the day but notices a dramatic drop-off as the dose effects subside. This effect is more evident with short-acting stimulants but can be seen with long-acting preparations, sometimes 8-11 hours after the dose is ingested. Treatment includes extending the patient's exposure to the stimulant. This can be accomplished either by adding a second dose of the long-acting stimulant 6 or 7 hours after the initial dose or by adding a booster dose of short-acting stimulant shortly before the rebound effect occurs. The appropriate booster medication is included for each agent in the Table. This phenomenon is rarely seen with atomoxetine. Blood pressure. Another potential issue to consider is how stimulant treatment can affect blood pressure and heart rate. According to the FDA in 2007,[19,23] stimulant medications may cause a modest increase in average blood pressure (about 2-4 mm Hg) and average heart rate (about 3-6 bpm). Physicians treating individuals with ADHD medication should include blood pressure and heart rate monitoring as a routine part of treatment. Clinicians also have expressed concerns over how to treat a patient with preexisting hypertension who presents for ADHD treatment. Wilens and colleagues[25] examined the use of extended-release mixed amphetamine salts (MAS XR) in adults with both ADHD and controlled primary essential hypertension. Thirteen patients were administered MAS XR with established antihypertensive medications for 6 weeks. Their blood pressures were monitored for 2 weeks after discontinuing MAS XR. In all 13 participants, mean systolic and diastolic blood pressure remained stable through the length of the study. Furthermore, during and immediately after the study, no participant required a higher dose of antihypertensive medication. Further study is warranted, but clinical experience suggests that treated essential hypertension is not a contraindication for stimulant use. Urinary retention. Urinary retention and urinary hesitancy in men and boys are issues to consider with the use of atomoxetine. In clinical trials, 9 out of 540 participants (1.7%) who received atomoxetine experienced urinary retention and 30 out of 540 (5.6%) experienced urinary hesitancy. Only 2 subjects discontinued because of these symptoms.[26] Although these urinary side effects tend to linger, symptom intensity usually responds to dose reduction. At times, even this does not reverse the symptoms and so transition to another ADHD medication is advised. This adverse event is not commonly seen with stimulants. ConclusionJason's presentation is characteristic of an adult diagnosed with ADHD in his third decade. Often, the adult receives prolonged and ineffective treatment for depression before the correct diagnosis is identified. The patient's response to the diagnosis and treatment typifies the obstacles that treating clinicians face. Jason demonstrates psychological resistance, which can usually be countered with patience, empathy, and psychoeducation. Most patients prescribed ADHD medications thrive, and clinicians soon learn that treating these patients is a singularly gratifying experience. Inevitably, some will encounter adverse events that demand a nimble clinical response. I hope that this article provides the reader an effective framework. |
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Managing Adverse Effects to Optimize Treatment for ADHD |
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IntroductionAttention-deficit/hyperactivity disorder (ADHD) begins in early childhood, and at least 50% of children will go on to have symptoms and impairment in adulthood.[1] Treatment requires a combination of medication and counseling, and adherence to medication therapy is essential for good outcomes. Managing adverse effects is a key component of effective treatment. Diagnosis and treatment of psychiatric comorbidity, which is common, is another essential aspect of care. This review will examine common adverse effects, prescribing medication successfully, deciding when to switch to an alternative medication, and some aspects of using concomitant medication. Initiating TreatmentDiagnosisAccording to the text revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the diagnosis of ADHD requires symptom onset before age 7 years. When evaluating children, parent and teacher input is essential and easy to obtain. Although some investigators have suggested that adult-onset ADHD is possible,[2] a full evaluation of an adult involves attempts to document symptoms and impairment in childhood. Interviews with parents and examination of school or medical records are often helpful. Monitoring treatment success requires documentation of baseline functional impairment. In adults, collateral interviews with partners or even coworkers, with the patient's permission, may be illuminating. Adults with ADHD experience important consequences from their impaired functioning. In a case-control study of 500 adults, those with ADHD had lower educational attainment, less job stability, lower incomes, and less successful relationships.[3] The evaluating clinician should investigate all of these areas. The other essential aspect of evaluation is screening for comorbidity. In many cases, ADHD is not the chief complaint but comes to light during evaluation of another symptom. The most prevalent comorbid conditions are depression, bipolar disorder, and anxiety disorders.[4] Substance-use disorders including nicotine dependence are also more common in people with ADHD than in the general population. Patient EducationOnce the diagnosis is established, the physician should explain the implications and the proposed treatment plan. Educating patients and families about both the therapeutic and adverse effects of pharmacotherapy will help them know what to expect. Describing the benefits of treatment, including possible improvements in psychosocial outcomes, will allow a fully informed decision. After learning about the side-effect profile of psychostimulants, a few patients who are ambivalent about medication may reject that treatment option. Nonstimulants should also be discussed to provide the full range of options, but the clinician should mention the trade-off of lower efficacy of nonstimulants compared with psychostimulants.[5] Once a patient has consented to a specific medication, the physician should explain the minimum trial duration necessary to determine a response and the dose-adjustment schedule. Clearly worded written information about the medication is usually appreciated by patients and their families. The informed-consent process should be documented. Managing Adverse EffectsThe common adverse effects of treatment are inherent in the pharmacodynamics of stimulant medication. Enhanced catecholamine neurotransmission in the central and autonomic nervous systems can cause insomnia, anorexia, and increased heart rate and blood pressure. These effects are most noticeable at the outset of treatment and after increases in dose. Patients often adjust to them during the ensuing weeks but may require encouragement during that interval. InsomniaStudies show that adults and children with untreated ADHD experience sleep anomalies compared with control subjects. A review of sleep studies of unmedicated children found evidence of more nocturnal motor activity and daytime somnolence compared with controls.[6] An actigraphic study of 33 adults with ADHD and 39 control subjects found similar differences between the groups at baseline, and sleep latency was prolonged in the ADHD subjects.[7] After treatment with methylphenidate, the adult patients continued to experience prolonged sleep latency and less total sleep duration, but sleep efficiency improved. In a study that used the most comprehensive method of evaluating sleep, polysomnography in a sleep lab, 34 untreated adults with ADHD had increased nocturnal activity, reduced sleep efficiency, more awakenings, and reduced REM sleep compared with control subjects.[8] For 10 patients who were treated with open-label methylphenidate, repeat polysomnography showed better sleep efficiency, and the patients also reported improved restorative value of sleep. Clinicians can conclude from these studies that the effect of medication on sleep may be beneficial in at least some patients, but further research with more subjects and with a variety of medications is needed. The fact remains that many patients treated with psychostimulants complain of initial insomnia, so an approach to manage this problem is necessary. Clinicians should document sleep patterns and complaints before treatment to help interpret problems that may arise after medication is prescribed. Sleep hygiene, consisting of simple behavioral approaches to promote sound sleep (eg, creating a restful environment and avoiding caffeine), is an inexpensive intervention for all patients with insomnia. In a study of initial insomnia in 27 children 6-14 years treated for ADHD with psychostimulants, the researchers provided a sleep hygiene intervention to which 5 of the children responded.[9] They randomly assigned the nonresponders to either 5 mg of melatonin or placebo. Adverse effects of placebo and melatonin were not significantly different. The investigators found the combination of sleep hygiene and melatonin to be safe and effective, with an effect size of 1.7. Although comparable randomized, controlled trial data do not exist for adults, mirtazapine has been reported as safe and effective for adults taking psychostimulants.[10] Atomoxetine may have an effect on sleep that is different from that of psychostimulants, including reduced sleep latency but less efficiency. In a randomized, double-blinded, crossover trial, methylphenidate treatment for children with ADHD caused more initial insomnia but fewer awakenings compared with atomoxetine treatment.[11] Switching to atomoxetine may be considered for patients who prefer it or who do not respond to adjunctive interventions for stimulant-associated insomnia. Appetite and GrowthAppetite reduction is common with psychostimulants and also can occur with nonstimulants, including atomoxetine and bupropion. This may be accompanied by nausea and abdominal pain in some patients. Some adults treated with psychostimulants may regard appetite suppression with resultant weight loss as beneficial. With long-acting stimulants, appetite returns later in the day. Simple approaches to this problem include eating breakfast before taking medication. Having food in the stomach may also help reduce abdominal symptoms. Children in particular should have a nutritious, high-calorie snack in the evening if their food intake has been low since breakfast. However, parents should be warned to monitor evening intake of empty calories, such as candy and chips. Weight loss or a downward shift of weight percentile is typical in children treated with psychostimulants. Short-term reduction in height growth rate during the initial 1-3 years of treatment with psychostimulants is well documented. In a literature review article, Poulton[12] concluded that a mean 1 cm/year deficit in height occurs during that interval. Less conclusive findings included a possible negative correlation between dose and growth, greater growth effect from dextroamphetamine than from methylphenidate, and rebound in growth of height and weight after discontinuation of stimulants. More controversial is the effect on final stature. According to Poulton, "It would appear that most children achieve a satisfactory adult height, but there may be an important subgroup whose growth is permanently attenuated."[12] Clinicians must discuss this with parents, many of whom will already have some concerns about the issue, and monitor children's height and weight, ideally at each visit. Research on atomoxetine is less comprehensive, but available evidence suggests a short-term downward shift in height and weight percentile. The effect on height may be minimal,[13] but longer-term studies are needed. In a child or adult with worrisome weight loss, or if a child's parents are anxious about growth deceleration, switching to another medication should be considered. Substituting methylphenidate for amphetamine would be more rational than substituting amphetamine for methylphenidate, but a nonstimulant is more likely to be ameliorative. Affective SymptomsIrritability, dysphoria, and (rarely) suicidal ideation can occur during treatment of ADHD.[14] Atomoxetine carries an FDA warning of a 0.4% incidence of suicidal ideation that has occurred in children during the first month of therapy.[15] No completed suicides have been reported, but discontinuation of atomoxetine is indicated if suicidal thoughts emerge. Minor mood changes and irritability occur with both psychostimulants and atomoxetine. Little evidence is available to guide intervention, but if the symptom is severe, the clinician may consider dose reduction, switching to an alternative psychostimulant, or trying an antidepressant nonstimulant such as bupropion or nortriptyline. Psychosis and ManiaAs dopamine transmission agonists, psychostimulants at excessive and prolonged doses would be expected to provoke psychotic symptoms or mania. These are well-reported but uncommon adverse effects during treatment in children, with an incidence estimated at 0.25%.[16] Emergent delusions, hallucinations, mania, or disorganized behavior requires treatment discontinuation. Most such symptoms resolve, but in a few cases, a bipolar disorder may be unmasked, which takes treatment priority. Cardiovascular EffectsPsychostimulants cause increased heart rate and blood pressure in adults and children. The effect is mild in most cases, but in adults, some patients with borderline baseline blood pressure may develop frank hypertension. In a 24-month study of 223 adults treated with mixed amphetamine salts, 5 subjects developed hypertension and 2 experienced palpitations or tachycardia that required medication discontinuation.[17] In a manufacturer-sponsored review of clinical-trial data, atomoxetine was found to cause small but clinically insignificant effects on blood pressure and heart rate in children, adolescents, and adults.[18] Treatment discontinuation for these effects was necessary only in a few adults. In managing any patient on psychostimulants or atomoxetine, clinicians should document pulse rate and blood pressure at baseline and every 6 months, with more frequent monitoring of patients with elevated risk for hypertension. A more controversial aspect of ADHD medications is the effect on cardiac conduction and the rare occurrence of sudden death. In an unpublished review of documented cases of sudden death in children and adults treated with stimulants or atomoxetine through 2005, many of these patients had an underlying cardiac anomaly discovered on autopsy or were taking other medications.[19] Furthermore, psychostimulants have little effect on the QTc interval. Data on atomoxetine are conflicting, with US trials suggesting no QTc effect.[14] A Europe-wide postmarketing surveillance study, however, found a small number of cases of QTc prolongation that resolved with medication discontinuation.[20] Whether a baseline electrocardiogram (ECG) is necessary for every patient is a matter of debate among specialists. Dr. David Goodman, an ADHD researcher and clinician, recommends specific screening for cardiac risk.[21] The 5 items he inquires about are history of spontaneous syncope, exercise-induced syncope, exercise-induced chest pain, sudden death in family members age 30 years and younger, and a family history of structural or electrical abnormalities. An ECG -- and in ambiguous situations, specialist consultation -- would be appropriate before initiating medication in older adults or any patient with risk factors. Complex PsychopharmacologyBecause comorbidity is common with ADHD, clinicians may prescribe psychostimulants with other medications, such as antidepressants, mood stabilizers, or antipsychotics. In fact, experienced psychopharmacologists often prescribe psychostimulants adjunctively for adults with treatment-resistant depression. Atomoxetine metabolism and a small portion of amphetamine metabolism involve CYP2D6, so caution is appropriate when combining these medications with fluoxetine, paroxetine, or fluvoxamine, which inhibit the enzyme. Tricyclic antidepressants have been safely prescribed with psychostimulants, although several case reports exist of increased adverse effects with the combination of imipramine and methylphenidate.[22] Psychostimulants combined with monoamine oxidase inhibitors may cause a hypertensive crisis; coadministration is contraindicated. The comorbidity of bipolar disorder and ADHD remains an area of active research and controversy. In a recent randomized, controlled trial, 40 children 6-17 years old with bipolar mania or hypomania and ADHD received divalproex for 8 weeks.[23] The 30 whose mood stabilized but who had active ADHD symptoms received mixed amphetamine salts. The researchers reported no significant adverse effects or worsening of mania. Similar controlled trials in adults are lacking, but in a retrospective study of 16 adult patients with bipolar disorder who were receiving methylphenidate, 5 patients had comorbid ADHD.[24] The others received a stimulant for depression. The patients were also taking various mood stabilizers, including divalproex, lithium, carbamazepine, lamotrigine, and second-generation antipsychotics. The investigators concluded that the practice was safe and effective, although "mild to moderate side effects" occurred, the single most common of which was irritability. ConclusionInitiating treatment with psychostimulants is no different from initiating other psychiatric medications. The key steps are:
Rare adverse effects, such as jaundice, skin reactions, vasculitis, and thrombocytopenia, are idiosyncratic, and routine testing for them is not cost-effective.[14] Any unusual complaints should prompt further investigation. Regular documentation of pulse and blood pressure (and growth in children) is mandatory. Most adverse effects can be managed by reassurance or dose reduction, but switching to a different agent may at times be necessary. Combining medications for comorbidities is justifiable and often safe if diagnoses and rationale are well documented, but evidence of efficacy is not well established |
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ADHD Complications |
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Psychostimulant Treatment and the Developing Cortex in Attention Deficit Hyperactivity DisorderShaw P, Sharp WS, Morrison M, et al This study examined whether stimulants for attention-deficit/hyperactivity disorder (ADHD) were associated with differences in cerebral cortex development. Study Design: Neuroanatomic MRI was used to assess the change in cortical thickness in 43 youths with ADHD; mean age at the first scan was 12.5 years, mean age at the second scan was 16.4 years. Of the 43 adolescents, 24 were treated with stimulants between scans while 19 were not treated between scans. Investigators included an additional comparison to a large sample of (n = 294) of typically developing control youths. Results: The rate of change of the cortical thickness in the right motor strip, the left middle/inferior frontal gyrus, and the right parieto-occipital region was different between the adolescents taking stimulants as compared with those not taking stimulants. Specifically, the study found more rapid cortical thinning in the group of patients not taking stimulants (mean cortical thinning of 0.16 mm/year [SD = 0.17], compared with 0.03 mm/year [SD = 0.11] in the group taking stimulants). Furthermore, comparison against the controls without ADHD showed that cortical thinning in the group not taking stimulants was in excess of age-appropriate rates. Conclusion: These findings show no evidence that stimulant treatment is associated with slowing of overall growth of the cortical mantle. Commentary: This is a remarkable paper from the Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, and the Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. The authors suggest that psychostimulant-induced improvements in cognition and action might foster cortical development within the normative range, as an example of activity-dependent neuroplasticity. The authors note that a randomized trial would be a better scientific design, but in the interim, this study shows the importance of comparisons with controls/normative data.Exercise Responses in Boys With Attention Deficit/Hyperactivity Disorder: Effects of Stimulant MedicationMahon AD, Stephens BR, Cole AS This study examined the effect of stimulants on exercise responses. Study Design: Exercise stress testing was conducted in this sample of boys, with and without medication, at a workload of 25 W, 50 W, and 75 W. Results: Submaximal heart rate (HR) was significantly higher by approximately 8-13 bpm, across all 3 intensities during the medication trial. Oxygen uptake (VO2), respiratory exchange ratio (RER), and perceived exertion were similar (P > .05). In the absence of medication, peak exercise, VO2, HR, and work rate were attenuated (P ≤ .05); decreased peak exercise responses were apparent in 6 of 13 participants. Conclusion: Without medication, physiologic responses at peak exercise are attenuated in some but not all boys with ADHD. Stimulant medication raises submaximal HR. There was no other effect on cardiorespiratory measures or perceived exertion. Commentary: This study is among a very limited number of papers assessing the cardiopulmonary impact of stimulant medications in individuals with ADHD. The majority of the safety information to date on stimulant medications relies on office based assessments of blood pressure (BP), HR, and electrocardiograms (ECG), taken at rest, as well as adverse event reporting in clinical trials and data claims review. Overall, the evidence points to small increases in HR and BP with no ECG changes, rare cardiovascular complaints, and no causal relationship with sudden death or other serious cardiovascular adverse event, in healthy children/adolescents/adults with ADHD. Examining cardiovascular response to exercise/exertion may shed additional light on this area. American Academy of Pediatrics/American Heart Association Clarification of Statement on Cardiovascular Evaluation and Monitoring of Children and Adolescents With Heart Disease Receiving Medications for ADHD: May 16, 2008American Academy of Pediatrics/American Heart Association The purpose of this joint advisory of the American Academy of Pediatrics (AAP) and the American Heart Association (AHA) is to clarify the recommendations. Study Design: Clinical recommendations. Results: On April 21, 2008, the AHA released a statement about cardiovascular evaluation and monitoring of children receiving drugs for the treatment of ADHD. As a result of language in the news release and the statement as published, there have been conflicting interpretations of the recommendations in regard to the use of an electrocardiogram (ECG) in assessing children with ADHD who may need treatment with medications. Conclusion: Obtaining a patient and family health history and performing a physical exam focused on cardiovascular disease risk factors (Class I recommendations) are recommended by the AAP and AHA for assessing patients before treatment with drugs for ADHD. However, acquiring an ECG is a Class IIa recommendation. This means that it is reasonable for a physician to consider obtaining an ECG as part of the evaluation of children being considered for stimulant drug therapy, but this should be at the physician's judgment; it is not mandatory. Commentary: It is critical for clinicians to review the updated clarification statement, in which the language concerning ECG recommendations has been altered. The AAP, the American Academy of Child and Adolescent Psychiatry, and the AHA concur that an ECG is not a recommended screening tool. Clinicians may refresh their approach to screening for children/adolescents with potential cardiovascular risk, based primarily on personal and family history, as well as physical/vital sign assessment. Any child/adolescent of concern may be referred to a cardiologist for further assessment. This approach is appropriate both before and during ADHD pharmacotherapy. Acute Atomoxetine Treatment of Younger and Older Children With ADHD: A Meta-analysis of Tolerability and EfficacyKratochvil CJ, Milton DR, Vaughan BS, Greenhill LL The purpose of this article is to describe the treatment response and tolerability of atomoxetine (ATX) in younger and older children with ADHD. Study Design: Researchers pooled data from 6 short-term (6-9 weeks) clinical trials. Subjects were 6-7 years of age (n = 280) or 8-12 years of age (n = 860); all had DSM IV-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS), Conners' Parent Rating Scale-revised subscales (CPRS-R:S), and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S). Results: ATX was superior to placebo (PBO) in both age categories for mean change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. With the exception of the CPRS-R:S Oppositional subscale, ATX-treated subjects in both the younger and older age groups demonstrated significant improvements compared with PBO on all efficacy measures. Response rates, defined as at least a 25% reduction from baseline in ADHD-RS total score, were significantly different between ATX and PBO treatment groups for children 6-7 years (ATX, 55.7%; PBO, 22.0%; P < .001) and children ages 8-12 years (ATX, 63.5%; PBO, 35.6%; P < .001). No statistically significant differential treatment effects were observed between the age groups (P = .287). Response rates, defined as having endpoint T-scores of < 65, were significantly different between ATX and PBO treatment groups for the 6- 7-year-olds (ATX, 44.3%; PBO, 16.5%; P < .0001) and the 8- to 12-year-olds (ATX, 51.9%; PBO, 28.4%; P < .0001). The treatment-by-age-group effect was not significant (P = .270). The percentage of subjects experiencing remission at endpoint, as defined by T-score < 60, were significantly different between ATX and PBO for both age groups (6- 7-year-olds: ATX 36.4%, PBO 8.8%, P < .0001; 8- to 12-year-olds, ATX 41.0%, PBO 19.8%, P < .0001). A significant treatment-by-age effect was seen (P = .0830) in remission rates. Although few subjects discontinued from either age group because of adverse events, a significant treatment-by-age-group interaction was observed for abdominal pain (younger: ATX = 19%/PBO = 6%; older: ATX = 15%/PBO = 13%; P = .044), vomiting (younger: ATX = 14%/PBO = 2%; older: ATX = 9%/PBO = 6%; P = .053). Conclusion: ATX is an effective and generally well-tolerated treatment for ADHD in both younger and older children. Overall, the response and tolerability of ATX treatment did not vary significantly between age groups. Commentary: The evidence base for ATX includes data from these 1000 children across 6 short-term trials, a sizeable number of children to examine in terms of efficacy and tolerability. Treatment response overall and tolerability did not significantly vary between ages. Onset of Efficacy of Long-acting Psychostimulants in Pediatric Attention-Deficit/Hyperactivity DisorderBrams M, Mao AR, Doyle RL This review provides an evidence-based description of the time course of efficacy of stimulant medications. Study Design: Authors conducted a literature search from 1998 to 2008 using a MEDLINE database and the keywords "attention-deficit/hyperactivity disorder," "extended-release," "sustained-release," "methylphenidate," "amphetamine," "randomized," "controlled," "placebo," "efficacy," "time course," and "classroom study." Studies were included if they met the following criteria: (1) randomized, blinded, placebo- or active comparator-controlled clinical studies; (2) extended-release (ER) formulation of a psychostimulant treatment for ADHD; and (3) at least 30 children and adolescents ages 6-17 years. Eighteen clinical trials met the chosen criteria. Medications evaluated included: (1) long-acting (LA) d, l-methylphenidate (MPH); (2) osmotic release (OR) d, l-MPH; (3) d, l-MPH-CD (MCD); (4) d-MPH-ER; (5) MPH transdermal system (MTS); (6) mixed amphetamine salts ER (MAS-XR); (7) lisdexamfetamine dimesylate (LDX). Results: Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at 1-2 hours, MCD at 1.5 hours, d, l-MPH-OR at 1-2 hours, MAS-XR at 1.5-2 hours, MTS at 2 hours, and LDX at approximately 2 hours. Duration of efficacy for each treatment was: MCD 7.5 hours; d, l-MPH-LA 8-12 hours; and 12 hours for MTS, d-MPH-ER, d, l-MPH-OR, MAS-XR, and LDX. Conclusion: d-MPH-ER has the earliest onset of efficacy at 0.5 hours post dose, and MTS, d-MPH-ER, d, l-MPH-OR, MAS-XR, and LDX have a long duration of action at 12 hours post dose. Commentary: Given the different trial designs and assessment timepoints, these studies are not directly comparable. However, it is important for clinicians to try to tailor ADHD treatment to an individual patient, inquiring about periods in the day (morning hours, afternoon, evening) that may be most difficult, and then choosing a medication that will cover those times well. The Impact of Individual and Methodological Factors in the Variability of Response to Methylphenidate in ADHD Pharmacogenetic Studies From Four Different ContinentsPolanczyk G, Faraone SV, Bau CH, et al This study examined the association between individual polymorphisms and response to methylphenidate (MPH) in ADHD. Study Design: This paper is an analysis of 9 pharmacogenetic studies from 4 different continents. The analysis included: (1) evaluation of the role of methodologic aspects in the variability of ADHD symptom improvement between studies using meta-regression; and (2) assessment of individual characteristics of the subjects in the variability of ADHD symptom improvement using multivariate regression. Results: Of 5 factors considered, only the design of the study (open studies vs randomized controlled trials) was significantly associated with heterogeneity of results (P = .001). At the individual level, however, age (P < .001), comorbid oppositional defiant disorder (P < .001), and pretreatment scores (P < .001) were associated with change of ADHD scores with treatment. Conclusion: The joint analyses of pharmacogenetic studies are feasible and promising, as primary fixed variables such as the study site were not related to findings. However, analyses according to the design of the study must be conducted and the role of individual factors must be included in the assessment. Commentary: Pharmacogenetics examines the putative associations between genes and clinical response to medications. Pharmacogenetic study in ADHD may yield information relevant to clinicians, including a greater understanding of who responds best to a given medication or what the tolerability profile will be. This particular group of authors includes significant contributors to the field of ADHD research and spans multiple countries. Such a collaboration is critical to the development of large databases in order to have sufficient power to conduct such analyses. Free Drug Samples in the United States: Characteristics of Pediatric Recipients and Safety ConcernsCutrona SL, Woolhandler S, Lasser KE, et al This study examined the characteristics of recipients of free samples as well as potential safety issues related to distributing free samples. Study Design: The study population was 10,295 US residents younger than 18 years of age who were included in the 2004 Medical Expenditure Panel Survey, a nationally representative survey that includes questions on receipt of free drug samples. The authors performed bivariate and multivariate analyses to evaluate characteristics associated with receipt of 1 or more free drug samples (in 2004). Results: In all, 10% of children who received prescription medications and 4.9% of all children received 1 or more free drug samples in 2004. Routine access to healthcare (defined as 3 or more provider visits in 2004) was associated with receipt of free samples. Poor children (family incomes below 200% of the federal poverty level) were no more likely to receive free samples than were those from families with incomes of at least 400% of the poverty level (3.8% vs 5.9%). Children who were uninsured for part or all of the year were no more likely to receive free samples than were those who were insured all year (4.5% vs 5.1%); 84.3% of all sample recipients were insured. Atomoxetine (ATX) and mixed amphetamine salts (MAS) were among the top 15 most frequently distributed pediatric free samples in 2004. Both ATX and MAS were among agents that received new or revised black box warnings between 2004 and 2007. Conclusion: Free samples do not target the neediest children selectively, but they do carry significant safety considerations. Commentary: Little is known about free-sample distribution in pediatric populations. This article is an important reminder to clinicians across medical fields that samples present risks different from those of prescription medications received at a local pharmacy. Samples may not include current warnings or safety information, and the use of samples may appear to be associated with a "lax" attitude toward risks and bypass the pharmacists' safety checkpoint. In addition, packaging may not be the same in terms of child safety or other safety reminders. For example, the authors of this article cite a study of 35 high-use drug samples, in which 54% lacked child-resistant packaging or warnings that the packaging was not child-resistant, 40% lacked the instruction "Keep out of reach of children," and 91% lacked the instruction "In case of accidental overdose, seek professional assistance or contact a poison control center immediately." This activity is supported by an independent educational grant from Shire |
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