A Multidimensional Approach to Medication Selection in the Treatment of Children and Adolescents with ADHD

| August 5, 2007 | 0 Comments

by Atilla Turgay, MD, FRCPC

Dr. Atilla Turgay is from the University of Toronto and the Scarborough Hospital.

Disclosure: Dr. Turgay has received research grants from Eli Lilly, Janssen Ortho, Purdue, and Cell Tech and is on the advisory boards of Eli Lilly, Shire, Janssen Ortho, Purdue, and Pfizer.

Abstract

The objective of this paper is to outline clinical patient characteristics to individualize medication selection for children and adolescents with ADHD. The treatment guidelines and clinical parameters outlined in this paper are based on clinical research and evidence- and/or consensus-based guidelines for medication treatment of children and adolescents with ADHD and associated symptoms or comorbid disorders. Recommendations are made for medication selection in different clinical situations. The increased availability of ADHD medications over the past few years has provided a number of treatment options with longer symptom control and improved the remission or “multidimensional normalization” for ADHD patients. Selection of the most appropriate medication(s) for complicated cases may present a serious challenge in some situations. This paper outlines selected complicated cases and treatment options.

Key words: attention deficity hyperactivity disorder, ADHD, children, adolescents, conduct disorder, aggressive disorders, oppositional defiance disorder, anxiety disorders, depression, pharmacology

Introduction

Recent epidemiological studies have reported that the prevalence of attention deficit hyperactivity disorder (ADHD) is highest in childhood and decreases as age increases[1–4] However, most medications are only approved for children over the age of six. During the essential formative years in development, the medical treatment of ADHD is limited. The Centers for Disease Control conducted the National Survey of Children’s Health from 2003 to 2004 in which parents of approximately 100,000 children aged 4 to 17 years were interviewed. They were asked whether their children had ever been diagnosed with ADHD or received medication.1 Results of the survey indicated that the rate of lifetime childhood diagnosis of ADHD was 7.8 percent, while only 4.3 percent (or 55% of those with ADHD) had ever been treated with medication for the disorder.[1]

Most children do not “outgrow” ADHD symptoms. A large majority (60–85%) of children with ADHD will continue to meet criteria for the disorder during the teenage years.[2,3] Recently, the National Comorbidity Survey Replication screened a sample of 3,199 individuals aged 19 through 44 years and estimated the prevalence of adult ADHD is 4.4 percent.[4]

The concept of “goodness of fit” described by Turgay and Ansari[5] refers to the compatibility of the patient’s need for symptom improvement and remission/normalization and the medication(s) selected for treatment. It is hoped that when “goodness of fit” exists between the patient and medication, his or her key symptoms will improve in a relatively short time with no or minimum side effects and that the medication(s) selected will provide improvement or “normalization” of symptoms. Normalization of symptoms can be assessed through the use of ADHD symptom rating scales. The application of this principle to patient care requires a thorough knowledge of patient characteristics and also about drug profiles and comparisons. The objective of this paper is to provide descriptions of multiple dimensions clinically relevant to the process of medication selection for patients with ADHD.

Most of the guidelines and parameters for treatment of ADHD provide generalizable information about medication selection for certain groups of patients, such as ADHD patients with depression or tic disorders. This paper will provide a brief overview of established guidelines for treatment. This paper will also describe some of the patient characteristics or dimensions that are not addressed in the current publications or guidelines. The contents of this paper are consistent with the American and Canadian guidelines and practice parameters. The integration of general guidelines and practice parameters, such as the American Academy of Child and Adolescent Pychiatry (AACAP) Practice Parameters, with the multidimensional, patient-focused, clinical decision process in medication selection provided in this paper may enhance the likelihood of finding the best medication(s) for the patient considered for treatment. Table 1 lists the dimensions. Case summaries will also be included to provide more comprehensive information about several of these dimensions.

Brief Overview of Current Guidelines

In 2004, the European clinical guidelines for hyperkinetic disorder were published.[6] These guidelines provided a leading role in the increasing interest in ADHD in Europe. The AACAP recently published practice parameters for the assessment and treatment of children with ADHD.[7] The parameters review epidemiological, genetic, and clinical features in addition to comorbid disorders and rating scales used in diagnosis. They also outline treatment options and provide guidelines and dosages for medications used in ADHD. The parameters also review treatment options for groups of ADHD patients and makes recommendations, including dosages for different age groups and side effect differences. Physicians who prescribe ADHD medications should be familiar with these guidelines and recommendations.

Canadian ADHD clinicians and researchers have recently published the Canadian ADHD Practice Guidelines.8 These guidelines provide step-by-step diagnostic guidelines with samples of rating scales used by clinicians in evaluating ADHD and its associated functional impairments. They also provide a general review of ADHD medications available in Canada.

The Texas Children’s Medication Algorithm Project provides guidelines for medication choices for ADHD simple and ADHD complex with comorbid disorders. Pliszka, et al., recommends starting the treatment of single ADHD without comorbid disorders with a stimulant (methylphenidate or amphetamine) as the first stage in treatment.[9] If this stimulant does not produce a satisfactory result, then stage 2 would be the use of the stimulant not used in stage 1. Stage 3 is a trial with atomoxetine, the nonstimulant ADHD medication, and stage 4 consists of a trial with antidepressants. The project provides algorithms for associated disorders, such as anxiety, depression, tics and aggressive behavior.

“ADHD Simple” vs “ADHD Complex”

The Canadian ADHD Resource Alliance established in 2006 that only one in five adolescents and adults with ADHD have only ADHD.[8] This Alliance refers to these patients as “ADHD Simple” and to others who have various comorbid disorders as “ADHD Complex.” Based on a sample of approximately 6000 subjects (children, adolescents and adults with ADHD), Turgay, et al.10 reported that almost all patients with ADHD who do not meet the full criteria for other DSM IV psychiatric disorders still have clinically significant symptoms interfering with functioning at home, school and work or in social life.

These symptoms are referred to as comorbid symptoms. They reported on the need for thorough screening for other important clinical target symptoms for treatment and medication selection. For example, patients with ADHD who are either underweight or overweight present complications in medication selection. Psychostimulants may decrease the patient’s weight, while imipramine, lithium, and risperidone may increase weight. Patients with ADHD with sleep initiation and/or maintenance problems of sleep may require different medication than patients with ADHD predominantly inattentive type who suffer from over-sleepiness during the day and early evening. Patients with ADHD plus aggression and/or self-injurious behavior who do not meet the diagnostic criteria for conduct disorder need special attention to this important “comorbid symptom” before the decision for medication selection is made.

Dimension 1. Age

In the United States, the only ADHD medications approved by the FDA for use in treating preschool children (age 3–5) are mixed amphetamine salts (Adderall®) and dextroamphetamine (Dexedrine® and DextroStat®). All other ADHD medications that are FDA-approved are for children age six and above. Some of the medications are approved for use in adults, while some are in the process of being approved. In Canada, no ADHD medications have been formally approved for treating children under the age of 6. The long-acting methylphenidate Biphentin,® atomoxetine (Strattera®), and mixed amphetamine salts (Adderall XR®) are approved in Canada for adults.

It is imperative that clinicians are aware of the approval status of each medication when prescribing it, as they must clearly inform patients and families about them. It is important to obtain written consent (with a witness present) and to carefully document in the patient’s medical file all ADHD medications that were previously tried (as recommended by the AACAP Practice Parameters[7]), but were not successful in improving the patient’s symptoms.

Clinician awareness about the age-specific features of different medications may improve treatment response, outcome, and lower the incidences and severity of side effects. This awareness may also improve adherence. Our knowledge in this area needs to be improved through further research with specific focus on age differences in medication treatment.

Prescribing medications that are not approved for a specific age group require detailed documentation in the patient’s medical file, including any experienced symptoms and their negative impact on the child, school, and family. Sufficient review of the approval status of the medication and existing evidence-based information with the parents (and signed consent in the medical file) is also necessary. There should be ample evidence published in scientific journals encouraging the use of the particular medication considered. As AACAP ADHD Parameters[7] indicate, the principle of using formally approved medications first is essential. The recent studies with children under the age of 6 years seem to be encouraging. Methylphenidate is found to be effective and safe for preschool children.[11] Case Example 1

Dimension 2. Duration of effect

Patients have different needs for the maintenance of their ADHD symptoms. There are also developmental differences of the impact of ADHD symptoms and dysfunction. In the individual patient evaluation, clinicians need to establish some clear understanding of the impact of ADHD and the relative interference it has on a 24-hour basis in order to determine the ideal duration of effect for the medication to be selected. Some preschool-age children may only need medication during the morning or afternoon school hours, while elementary school-age children may require duration of effect throughout the entire school day. High school and college students may prefer medications that provide symptom control during the day and evening (often when they are studying, writing papers, etc).

Table 2 outlines the mechanisms of action, duration of treatment effect, the ability to sprinkle medications on foods for patients who have difficulties swallowing pills, available doses, and maximum recommended daily doses. This table can be used in selecting the optimal medication for differing patient needs with various desired durations of effect. ADHD symptomatology and behavioral dysfunctions change across developmental stages. Many parents of young children prefer symptom control during school hours only; they often do not wish to administer medication that may interfere with the child’s appetite for dinner and/or delay sleep at night.

As demonstrated in Table 2, the duration of the desired effects of different medications are variable. Clinicians must determine the negative impact of ADHD symptoms and dysfunctions on individual patients and decide on the needed duration of effect from the ADHD medication. During which portion(s) of the day are the patient’s ADHD symptoms interfering with functioning at home and at school? Which ADHD symptoms remain in the evening after the desired effects of the psychostimulants have worn off? Can the patient also use a short-acting tablet of the same medication if the long-acting effects are not long enough? A careful analysis of specific needs of each patient and the duration of the desired effects should be completed in order to maximize benefits for individual patients. Dysfunctions associated with ADHD are not limited to school hours only. Family life and social life requires sufficient control of ADHD symptoms outside the school hours. Case Example 2

Dimension 3. The speed of action of the medication

Psychostimulants and non-stimulants work differently when it comes to the speed of action. If patients are given an appropriate psychostimulant dosage, the desired effects begin within 30 to 45 minutes. The norepinephrine reuptake inhibitor atomoxetine may typically require 4 to 16 weeks to maximize the desired effects, although research indicates that the clinical effects begin much earlier and may be perceived in some patients even after 6 to 7 days after the initiation of treatment.[12,13] Nonstimulant tricyclic antidepressants and clonidine may also require 4 to 12 weeks to maximize the desired effects. Mood-regulating medications may require at least 6 to 8 weeks to start the desired effects in controlling aggressive behavior, impulsivity, and mood swings. Many patients are in need of more immediate symptom control and may not be able to wait several weeks for their medications to take effect.[7-9]

Dimension 4. ADHD Subtypes

DSM IV identifies four subtypes of ADHD: combined type, predominantly inattentive type, hyperactive impulsive type, and ADHD not otherwise specified (NOS). Some ADHD subtypes may not respond to some medications. Clonidine is effective in treating ADHD combined type and hyperactive-impulsive type but does not improve ADHD predominantly inattentive type.[7, 14,15] ADHD hyperactive impulsive type and ADHD combined type are more frequently associated with oppositional defiant disorder, conduct disorder, and aggression, and medications that are effective in treating these comorbid disorders should be considered.[16]

Dimension 5. Comorbid symptom profile in medication selection

As outlined in this article, the review of associated behavior and comorbid disorders in ADHD is essential in the determination of the medication(s) for treatment. For example, the presence of aggressive behavior, poor driving habits, and poor work habits may have serious impact. Symptom checklists and rating scales can be utilized in assessing comorbid symptoms and disorders. In medication dosing and management, these associated symptoms need to be monitored in addition to the 18 core DSM-IV symptoms of ADHD. Some adolescent drivers with ADHD may not understand that their difficulties in driving and their high rates of accident proneness are related to their ADHD. This is a very significant associated behavior with potentially serious impacts. Recent reports indicate that ADHD medications are quite effective in improving driving in these patients. Unfortunately, some of the most effective ADHD medications cannot be used in the evening hours if they suppress sleep.

Dimension 6. Comorbid disorder profile guiding medication selection

Clinical studies with large samples of ADHD patients have established that ADHD is a multidimensional disorder with complicated associated symptoms and comorbid disorders.[10]

Only one in five patients with ADHD has ADHD alone; four out of five patients have another comorbid psychiatric disorder. The most common comorbid disorder with ADHD is oppositional defiant disorder (ODD). More than 60 percent of patients with ADHD also suffer from ODD.[8] The presence of oppositional defiant disorder, major depression or dysthymia, and anxiety disorder will affect medication selection. Approximately, 25 to 35 percent of patients with ADHD will have a coexisting learning or language problem, and anxiety disorders occur in up to one-third of patients with ADHD.[7–9]

The choice of medication is often influenced by the nature of the patient’s comorbid disorder(s) and which disorder(s) is currently the most functionally impairing. The presence of major depression and suicidal risk may require the use of antidepressant medications especially SSRIs with or without psychostimulants.[7,8,10] As illustrated in Table 3, ADHD subtypes and associated comorbid disorders change over time and by developmental stage.[10]

In early childhood, oppositional defiant disorder and communication disorders, including articulation disorder, are more common.[2,10] In adolescence, anxiety disorders, mood disorders, and substance abuse disorders are added to the overall clinical picture.[2,10] Most psychostimulants and atomoxetine are effective in controlling oppositional defiant disorder (ODD) symptoms associated with ADHD.[2,10] For some patients with ADHD, ODD, and verbal and physical aggression, the use of psychostimulants may improve all of these symptoms.[19,20] Atomoxetine treatment in children and adolescents with ADHD may also improve the symptoms of oppositional defiant disorder.[21,22]

The presence of comorbid disorders in a patient with ADHD make treatment more complicated and challenging. The treatment response to associated comorbid disorders differs according to the comorbidity profile. Psychostimulants and atomoxetine seem to have some differences in their effectiveness for different comorbidities. The positive effects of psychostimulants on oppositional behavior, impulsivity, and aggression may make them the first choice in medication selection for many patients. For the patients with substance use disorder or for the patients with high risk to abuse psychostimulants, atomoxetine may be a more appropriate choice. Atomoxetine seems to have more positive effects on anxiety and tic disorders associated with ADHD.[17] The AACAP ADHD Parameters and clinical studies emphasize this difference and suggest that atomoxetine may have a lower risk for aggravating tics than psychostimulants.[7,18,23]

Some patients may require separate treatment with both psychostimulants and atomoxetine to determine which medication controls ADHD, tics, and/or anxiety disorders. A recent literature review also supports that certain ADHD patients with multiple comorbidities like anxiety and depression may experience worsening of appetite and sleep suppression with psychostimulants; these patients may respond better to atomoxetine than psychostimulants.[23] Some patients with severe depression may require effective antidepressant treatment with or without ADHD medications.[6,8] Screening for disruptive behavior disorders, anxiety disorders, mood disorders, and substance abuse is essential before medication selection as the choice of medication is different for different associated comorbid disorders. When the anxiety symptoms or disorders are related to untreated ADHD rather than a separate comorbid disorder, children and adolescents with ADHD, anxiety, and/or tic disorders may also respond well to psychostimulants.[24] For patients with ADHD and major depression who do not respond to SSRIs, bupropion can also be considered since bupropion has positive effects in controlling depression and ADHD.[5] Some antidepressants, particularly those with strong sedating effects like paroxetine, may improve anxiety and depression in ADHD patients, but worsen problems with executive functioning. For the patients with depression, anxiety and ADHD SSRIs can be considered.

A comorbid diagnosis of mania should be considered in ADHD patients who exhibit severe mood lability/elation/irritability, thought disturbances (grandiosity, flight of ideas), severe aggressive outbursts (“affective storms”), and decreased need for sleep or age-inappropriate levels of sexual interest. ADHD patients may also present with mood variations and mood swings but these are transitional and not as severe and long-lasting as we see in bipolar patients. Hypomania should not be diagnosed solely on the basis of the severity of ADHD symptoms or aggressive behavior in the absence of the manic symptoms listed above. Acutely manic ADHD patients generally require mood stabilization before treatment of the ADHD.[7]

Older adolescents with ADHD should be screened for substance abuse disorders, as they are at greater risk than teenagers without ADHD for smoking, alcohol and substance abuse disorders.[10]

The role of new generation antipsychotic medication use, like risperidone, in patients with ADHD, oppositional defiant disorder, and aggressive behavior has been well established in the Texas Algorithm Project.[9] Short-term and long-term effectiveness and safety of risperidone in the treatment of oppositional defiant disorder and aggressive behavior in children has been well established through multisite, placebo-controlled studies.[25,26,28]

Psychostimulants may improve aggressive behavior in children and adolescents with ADHD.[27] Antipsychotic medications can be considered in the treatment of patients with ADHD with conduct disorder and uncontrollable aggression that presents risks for the safety of the patients and others when psychostimulants, atomoxetine, antidepressant medications, and psychosocial interventions do not improve aggressive behavior. These medications can also be considered for the patients with both ADHD and bipolar disorder when patients do not respond to mood stabilizers with or without ADHD medications. In this group, one of the best studied new generation antipsychotic medication is risperidone.[25,26,28] Multiple-site international studies with risperidone in children, adolescents, and adults established its safety and efficacy in various symptom domains including aggressive behavior.[25,26,28] Figure 1 provides an outline of symptoms across different diagnostic domains that respond well to risperidone.[25,26,28]

Risperidone seems to decrease anxiety, insecurity, and self-injurious behavior and aggression in children and adolescents with ADHD, oppositional defiant disorder, and conduct disorder and can be indicated for patients who are a danger to themselves and others and who do not respond to ADHD medications alone and psychosocial interventions.[25,26,28]

Conduct disorder symptoms and aggressivity improved within the first week in two US studies with an average dose of 1.16mg per day with risperidone 0.98mg per day.[25,26,28] A one-year follow-up study demonstrated that the gains were maintained with no major side-effects.[26] Case Example 3 Case Example 4 Case Example 5

Dimension 7. History of earlier medication use

Obtaining detailed history about the medications used in treating ADHD since the beginning of a patient’s treatment history will provide very useful information about the desired effect, side effects, and dose relationships. Often in earlier medication trials, the dose escalation was stopped before the maximum dose levels were reached or symptom remission or normalization was achieved. Knowledge of side effects a patient may have experienced with past trials of psychostimulants, e.g., suppression of appetite and sleep, can be obtained from the patient’s history of earlier medication use and guide the medication selection. Earlier successful treatment with either an amphetamine product or methylphenidate product may help the selection of a long-acting medication with one of these chemicals in the medication structure.

Dimension 8. Positive or Negative Attitudes Toward Medication

There has been extensive information in the media about ADHD medications and their use, safety, and efficacy. Ongoing reviews conducted by health authorities like the FDA and Health Canada and their European, Asian, and African counterparts are providing new information about the possible side effects and impact of ADHD medications. This often leaves patients and families in a difficult position because they may develop some bias/negative attitudes toward certain medications or groups of medications. Before prescribing any medication, it is important to talk about what the patients and their families know about ADHD medications and explore any biases they may have. It is important for physicians to review all feelings that the patients and their families have toward medication use as it may impact adherence and ultimately treatment outcome.

Dimension 9. Affordability Issues in Medication Selection

Although many publications and guidelines recommend longer acting medication over the immediate acting ADHD medications, the cost difference between these medications may present barriers and negatively impact the use of particular long-acting medications. It is advisable to openly discuss the cost of each treatment option and make the most appropriate recommendation based on the patient’s needs as well as on whether or not his or her family is able to afford the medication. It is this author’s believe that the longer acting medications save money in mental healthcare in the long run.

Dimension 10. Medical Conditions of the Patients to be Taken into Account in Medication Selection

The presence of cardiac problems, high/uncontrolled high blood pressure, and irregular pulse may limit the use of ADHD medications. For some patients with questionable EKG and cardiac conditions, a cardiology consultation may be required. The presence of hypo- or hyperthyroidism may require a consultation with an endocrinologist in the overall decision process. The presence of epilepsy and/or mental retardation in patients with ADHD requires special attention. Some of the medications used in epileptic patients or patients with asthma may also aggravate hyperactivity and inattention problems. In cases where the complexity of epilepsy and the selection of a medication that will not interfere with attention and executive functioning must be considered, a psychiatrist with expertise in ADHD medication treatment should also consult with a neurologist.

Dimension 11. The Presence of Clinical Symptoms Similar to Medication Side Effects Must be Considered in Medication Selection

Tics and sleep problems are common in ADHD. These are the most frequent side effects of psychostimulant medications. Some of the ADHD medications, like clonidine, may improve tics and present fewer problems with sleep suppression.[14,15] Tricyclic antidepressants are also sleep regulators and may decrease tics.[16] Atomoxetine can be considered for patients with ADHD and tic disorders.[17,18] Clinicians should be careful not to prescribe medications with side effects that may worsen already existing associated features of ADHD.

Dimension 12. Combinability with Other Medications

Many ADHD patients, more specifically the patients with multiple disorders, may require more than one medication. Although limited, there is some information about the safety of the combination of commonly used ADHD medications. There has been a long-term combined use history of psychostimulants with antidepressants to enhance the antidepressant effects of antidepressant medications. Risperidone combination with psychostimulants (amphetamine and methylphenidate) and atomoxetine combination with fluoxetine, psychostimulants, and fluoxetine has been studied.[5,16,21–23,26–28]

When a clinician feels that a second medication is needed, it is wise to start with the ADHD medication that has been combined safely with the second medication being considered. For the selection of ADHD medication for children and adolescents with severe conduct disorder and aggressive behavior, it is wise to start with psychostimulants as their combinability with risperidone may be required if the aggression is not controlled with psychostimulants alone.28 For the patients with major depression and ADHD, fluoxetine can be considered since this is the only FDA approved medication for major depression in children and adolescents.

Dimension 13. Physician Attitude toward ADHD Medications

Consultants working with primary care physicians may need to know prescribing physicians’ knowledge, experience, and attitudes toward ADHD medications, their dose escalation, and their comfort with the maximum dose levels, especially when patients indicate physician unwillingness to prescribe medications. Healthy, triangular trusting relationships between prescribing physicians, patient, family, and consultants are essential in reaching objectives in treatment.[29] Lack of information about certain medications and negative bias by physicians need to be addressed to maximize the positive effects of the use of medication. Physician discomfort related to new medications may require an active involvement of the experienced consultant to provide patient-based education for the primary care physician. Negative attitude of the physician will not help the patient and family who already have some skepticism about the particular medication.

Conclusions

In the treatment of ADHD and associated comorbid disorders, the effectiveness and safety of different ADHD medications has been well established. Clinicians are faced with selecting the most appropriate medication that would provide the “goodness of fit” with certain patient characteristics like age, comorbid disorders or comorbid symptoms not listed among the essential features of ADHD. A general review of the multiple clinical dimensions outlined in this paper may provide a clinically useful systematic review of the patient characteristics to find the “best fit” with the medication(s) to be selected for the treatment of ADHD and associated disorders. The differential use of these medications needs further clarification through evidence-based research and head-to-head comparisons.

The determination of the frequency, nature and severity of comorbid psychiatric symptoms and disorders and monitoring the response of these to medication treatment may improve the outcome and improve the quality of life of children and adolescents with ADHD and those around them.

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