Tanya E. Froehlich, MD, MS

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, affecting 8% to 12% of school-aged children in the United States^1-3 with significant impairments that often persist into adulthood.^4-8 Current guidelines recommend stimulant medication and/or behavioral therapies as first-line treatments for ADHD.^9,10 There is a wealth of evidence on the efficacy of stimulants in ADHD, with the most significant effects noted on core ADHD symptoms.^11,12 Additional evidence links stimulants to decreased long-term negative outcomes, including reduced school absences and grade retention,¹³ as well as modestly but significantly improved reading and math scores.¹⁴ Other studies have reported that individuals with ADHD who receive medication have decreased criminality,^15,16 motor vehicle accidents,^17,18 injuries,¹⁹ substance abuse,^20-22 and risk for subsequent and concurrent depression.²³ Therefore, the evidence suggests that consistent medication treatment helps improve outcomes for individuals with ADHD.

Adherence is defined as “the extent to which a person’s behavior (eg, taking medication) corresponds with agreed recommendations from a clinician.”²⁴ Unfortunately, pediatric ADHD medication adherence has been found to be poor (approximately 64%).^25-30 Nonadherence to ADHD medication has been linked to multiple factors, including caregiver/family and child/adolescent factors (Table 1), medication-related factors (Table 2), and health care/system factors (Table 3). Understanding and addressing these factors is essential to maximizing long-term outcomes. In this article, we review the factors associated with nonadherence to ADHD medication, and outline strategies to improve adherence.

Caregiver/family characteristics

Caregiver beliefs about ADHD and their attitudes toward treatment have been associated with the initiation of and adherence to ADHD medication. For example, caregivers who view a child’s difficulties as a medical disorder that requires a biologic intervention are more likely to accept and adhere to medication.³¹ Similarly, caregivers who perceive ADHD medication as safe, effective, and socially acceptable are more likely to be treatment-adherent.^32-35Other caregiver-related factors associated with improved ADHD medication adherence include:

• increased caregiver knowledge about ADHD³³
• receiving an ADHD diagnosis based on a thorough diagnostic process (ie, comprehensive psychological testing)³⁶
• satisfaction with information about medicine
• comfort with the treatment plan.³⁴

Socioeconomic status, family functioning, and caregiver mental health diagnoses (eg, ADHD, depression) have also been linked to ADHD medication adherence. Several studies, including the Multimodal Treatment Study of Children with ADHD,¹¹ a landmark study of stimulant medication for children with ADHD, have found an association between low income and decreased likelihood of receiving ADHD medication.^2,37-39 Further, Gau et al⁴⁰ found that negative caregiver-child relationships and family dysfunction were associated with poor medication adherence in children with ADHD.⁹ Prior studies have also shown that mothers of children with ADHD are more likely to have depression and/or anxiety,^41,42 and that caregivers with a history of mental health diagnoses are more accepting of initiating medication treatment for their children.⁴³ However, additional studies have found that caregiver mental health diagnoses decreased the likelihood of ADHD medication adherence.^40,44

Child characteristics

Child characteristics associated with decreased ADHD medication adherence include older age (eg, adolescents vs school-aged children),^{29,30,34,40,45-47} non-White race, Hispanic ethnicity,^29,33,48-51 female gender,^29,33,52 lower baseline ADHD symptom severity,^30,37 and child unwillingness to take medications.³⁴ However, prior studies have not been completely consistent about the relationship between child comorbid conditions (eg, oppositional defiant disorder [ODD], conduct disorder) and ADHD medication adherence. A few studies found that child comorbid conditions, especially ODD, mediate poor ADHD medication adherence, possibly secondary to an increased caregiver-child conflict.^30,53,54 However, other studies have reported that the presence of comorbid ODD, depression, and anxiety predicted increased adherence to ADHD medications.^37,46

Medication-related factors

Adverse effects of medications are the most commonly cited reason for ADHD medication nonadherence.^5,33,54-56 The adverse effects most often linked to nonadherence are reduced weight/appetite, increased aggressive behavior/irritability, and sleep difficulties.^54,57 Studies comparing methylphenidates and amphetamines, including 2 recent meta-analyses, suggest that amphetamines may be less well-tolerated on average, particularly with regard to emotional lability and irritability.^45,58,59 Therefore, clinicians might consider using methylphenidate-based preparations as first-line psychopharmacologic interventions in children with ADHD, as is consistent with the findings and conclusions drawn by a recent systematic review and meta-analysis of the comparative efficacy and tolerability of ADHD medications.⁶⁰

On the other hand, increased ADHD medication effectiveness has been associated with improved medication adherence.^5,34,54-56 Medication titration and dosing factors have also been shown to affect adherence. Specifically, adherence has been improved when ADHD medications are titrated in a systematic manner soon after starting treatment, and when families have an early first contact with a physician after starting medication (within 3 months).²⁸ In addition, use of a simplified dose regimen has been linked to better adherence: patients who are prescribed long-acting stimulants are more likely to adhere to treatment compared with patients who take short-acting formulations.^{26,40,49,61-63} It is possible that long-acting stimulants increase adherence because they produce more even and sustained effects on ADHD symptoms throughout the day, compared with short-acting formulations.⁶⁴ Furthermore, the inconvenience of taking multiple doses throughout the day, as well as the potential social stigma of mid-school day dosing, may negatively impact adherence to short-acting formulations.¹⁰

Continue to: Health care/system factors

Several studies have investigated the influence of health services factors on ADHD medication adherence. Specifically, limited transportation services and lack of mental health providers in the community have been linked to decreased ADHD medication adherence.^47,65,66 Furthermore, limited insurance coverage and higher costs of ADHD medications, which lead to substantial out-of-pocket payments for families, have been associated with decreased likelihood of ADHD medication adherence.^29,67

Clinician-related factors also can affect ADHD medication adherence. For example, a clinician’s lack knowledge of ADHD care can negatively impact ADHD medication adherence.⁶⁸ Two studies have documented improved ADHD medication adherence when treatment is provided by specialists (eg, child psychiatrists) rather than by community primary care providers, possibly because specialists are more likely to provide close stimulant titration and monitoring (ie, ≥ 3 visits in the first 90 days) and use higher maximum doses.^62,69 Furthermore, ADHD medication initiation and adherence are increased when patients have a strong working alliance with their clinician and trust the health care system,^31,34,35 as well as when there is a match between the caregiver’s and clinician’s perception of the cause, course, and best treatment practices for a child’s ADHD.⁶⁵

Strategies to improve medication adherence

A number of strategies to improve ADHD medication adherence can be derived from our knowledge of the factors that influence adherence.

Patient/family education. Unanswered questions about ADHD diagnosis, etiology, and medication adverse effects can negatively impact the ADHD treatment process. Therefore, patient/family education regarding ADHD and its management is necessary to improve medication adherence, because it helps families attain the knowledge, confidence, and motivation to manage their child’s condition.

Clinicians have an important role in educating patients about⁷⁰:

• the medications they are taking
• why they are taking them
• what the medications look like
• the time of medication administration
• the potential adverse effects
• what to do if adverse effects occur
• what regular testing/monitoring is necessary.

Clinicians can provide appropriate psychoeducation by sharing written materials and trusted websites with families (see Related Resources).

Behavioral strategies. Behavioral interventions have been among the most effective strategies for improving medication adherence in other chronic conditions.⁷¹ Behavioral strategies are likely to be particularly important for families of children with ADHD and comorbid conditions such as ODD because these families experience considerable caregiver-child conflict.⁷² Moreover, parents of children with ADHD are at higher risk for having ADHD and depression themselves,⁷³ both of which may interfere with a parent’s ability to obtain and administer medications consistently. Thus, for these families, using a combination of psychoeducation and behavioral strategies will be necessary to affect change in attitude and behavior. Behavioral strategies that can be used to improve medication adherence include:

• Technology-based interventions can reduce the impact of environmental barriers to adherence. For example, pharmacy automatic prescription renewal systems can reduce the likelihood of families failing to obtain ADHD medication refills. Pill reminder boxes, smartphone alerts, and setting various alarms can effectively prompt caregivers/patients to administer medication. In particular, these methods can be crucial in families for which multiple members have ADHD and its attendant difficulties with organization and task completion.
• Caregiver training may assist families in developing specific behavioral management skills that support adherence. This training can be as straightforward as instructing caregivers on the use of positive reinforcement when teaching their children to swallow pills. It may also encompass structured behavioral interventions aimed at training caregivers to utilize rewards and consequences in order to maximize medication adherence.⁷⁴

Continue to: Clinician interventions

Clinician interventions. Clinicians can use decision aids to help inform families about treatment options, promote shared decision making, and decrease uncertainty about the treatment plan⁷⁵ (see Related Resources). Early titration of ADHD medications and early first contact (within months of starting medication treatment) between caregivers and clinicians, whether via in-person visit, telephone, or email, have also been related to improved adherence.²⁸ Furthermore, clinicians can improve adherence by prescribing a simplified medication regimen (ie, long-acting formulations that provide full-day coverage). To address the negative impact of high out-of-pocket ADHD medication costs on adherence, clinicians can also prescribe generic preparations and/or “preferred” medications options on an individual patient’s formulary.

Because clinician knowledge and expertise in ADHD care has been linked to improved patient medication adherence,⁶⁸ clinicians are encouraged to use the American Academy of Pediatrics (AAP) guideline for diagnosis and treatment of ADHD, which includes a supplemental process of care algorithm (last published in 2011,¹⁰ with an updated guideline anticipated in 2019), as well as the AAP/National Institute for Children’s Health Quality (NICHQ) ADHD Toolkit,⁷⁶ which includes items helpful for ADHD diagnosis and treatment. The Society for Developmental and Behavioral Pediatrics is also developing a clinical practice guideline for the diagnosis and treatment of complex ADHD (ie, ADHD complicated by coexisting mental health, developmental, and/or psychosocial conditions or issues), with publication anticipated in 2019. Primary care providers can also improve their expertise in ADHD care by pursuing additional mental health–related trainings (such as those conducted by the REACH Institute).⁷⁷

Because receiving ADHD care from a specialist has been shown to improve medication initiation and adherence,^62,69 other strategies to address the short supply of child psychiatrists include offering incentives to medical students to pursue a career in child psychiatry (eg, loan forgiveness). Telepsychiatry and co-location of mental health specialists and primary care providers are additional innovative ways in which ADHD specialty care can be delivered to more patients.⁶⁴

Finally, providing culturally-sensitive care can strengthen the clinician-caregiver relationship and promote adherence to treatment. For example, clinicians can partner with local groups to increase their understanding of how different racial/ethnic groups perceive ADHD and its treatment.⁶⁴

Peer support models. Peers are credible role models who have a valued role in facilitating the use of mental health services by empowering families and enhancing service satisfaction.⁷⁸ In several communities in the United States, peer models using family advocates have been introduced.⁷⁹ Family advocates are typically caregivers of children who have special needs or have been involved in the mental health system. Their perspective—as peers and first-hand consumers of the health care and/or mental health system—can make them powerful and effective coaches to families of children with ADHD. By helping families to navigate ADHD care systems successfully, family advocates can play an important role in enhancing ADHD medication adherence, although further investigation is needed. In addition, the stigma around ADHD medication use, which adversely impacts adherence, can be mitigated if caregivers participate in organized ADHD-related support groups (eg, Children and Adults with ADHD [CHADD]).

Continue to: Health disparity-reducing interventions

Health disparity-reducing interventions. Successful health disparity-reducing interventions—such as those developed to enhance care of other chronic disorders including asthma and diabetes—can be applied to improve ADHD care. These interventions, which include medical-legal partnerships (eg, between clinicians, social workers, legal advocates, and community partners) in primary care centers, have been shown to improve health insurance coverage and therefore health care access.^80,81 Although some hardships linked to nonadherence (eg, low socioeconomic status) may not be amenable to health care–related interventions, screening for these hardships can identify children who are most at risk for poor adherence. This would alert clinicians to proactively identify barriers to adherence and implement mitigation strategies. This might include developing more streamlined, easier-to-follow management plans for these patients, such as those that can be delivered through pharmacist-physician collaborative programs⁸² and school-based therapy programs.^83-85

Bottom Line

Suboptimal adherence to medications for attention-deficit/hyperactivity disorder (ADHD) can be addressed through patient/family education, behavioral strategies, clinician interventions, peer support models, and health disparity-reducing interventions. By improving ADHD treatment adherence, these interventions have the potential to maximize long-term outcomes.

Related Resources

• Cohen Children’s Medical Center Northwell Health. The ADHD Medication Guide. www.ADHDMedicationGuide.com. Revised December 31, 2017.
• Cincinnati Children’s Hospital Medical Center. Decision aids to facilitate shared decision making in practice. www.cincinnatichildrens.org/service/j/anderson-center/ evidence-based-care/decision-aids.
• CHADD. Children and Adults with attention-deficit/ hyperactivity disorder. www.chadd.org.

Drug Brand Name

Methylphenidate • Concerta, Ritalin

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, affecting 8% to 12% of school-aged children in the United States^1-3 with significant impairments that often persist into adulthood.^4-8 Current guidelines recommend stimulant medication and/or behavioral therapies as first-line treatments for ADHD.^9,10 There is a wealth of evidence on the efficacy of stimulants in ADHD, with the most significant effects noted on core ADHD symptoms.^11,12 Additional evidence links stimulants to decreased long-term negative outcomes, including reduced school absences and grade retention,¹³ as well as modestly but significantly improved reading and math scores.¹⁴ Other studies have reported that individuals with ADHD who receive medication have decreased criminality,^15,16 motor vehicle accidents,^17,18 injuries,¹⁹ substance abuse,^20-22 and risk for subsequent and concurrent depression.²³ Therefore, the evidence suggests that consistent medication treatment helps improve outcomes for individuals with ADHD.

Adherence is defined as “the extent to which a person’s behavior (eg, taking medication) corresponds with agreed recommendations from a clinician.”²⁴ Unfortunately, pediatric ADHD medication adherence has been found to be poor (approximately 64%).^25-30 Nonadherence to ADHD medication has been linked to multiple factors, including caregiver/family and child/adolescent factors (Table 1), medication-related factors (Table 2), and health care/system factors (Table 3). Understanding and addressing these factors is essential to maximizing long-term outcomes. In this article, we review the factors associated with nonadherence to ADHD medication, and outline strategies to improve adherence.

Caregiver/family characteristics

Caregiver beliefs about ADHD and their attitudes toward treatment have been associated with the initiation of and adherence to ADHD medication. For example, caregivers who view a child’s difficulties as a medical disorder that requires a biologic intervention are more likely to accept and adhere to medication.³¹ Similarly, caregivers who perceive ADHD medication as safe, effective, and socially acceptable are more likely to be treatment-adherent.^32-35Other caregiver-related factors associated with improved ADHD medication adherence include:

• increased caregiver knowledge about ADHD³³
• receiving an ADHD diagnosis based on a thorough diagnostic process (ie, comprehensive psychological testing)³⁶
• satisfaction with information about medicine
• comfort with the treatment plan.³⁴

Socioeconomic status, family functioning, and caregiver mental health diagnoses (eg, ADHD, depression) have also been linked to ADHD medication adherence. Several studies, including the Multimodal Treatment Study of Children with ADHD,¹¹ a landmark study of stimulant medication for children with ADHD, have found an association between low income and decreased likelihood of receiving ADHD medication.^2,37-39 Further, Gau et al⁴⁰ found that negative caregiver-child relationships and family dysfunction were associated with poor medication adherence in children with ADHD.⁹ Prior studies have also shown that mothers of children with ADHD are more likely to have depression and/or anxiety,^41,42 and that caregivers with a history of mental health diagnoses are more accepting of initiating medication treatment for their children.⁴³ However, additional studies have found that caregiver mental health diagnoses decreased the likelihood of ADHD medication adherence.^40,44

Child characteristics

Child characteristics associated with decreased ADHD medication adherence include older age (eg, adolescents vs school-aged children),^{29,30,34,40,45-47} non-White race, Hispanic ethnicity,^29,33,48-51 female gender,^29,33,52 lower baseline ADHD symptom severity,^30,37 and child unwillingness to take medications.³⁴ However, prior studies have not been completely consistent about the relationship between child comorbid conditions (eg, oppositional defiant disorder [ODD], conduct disorder) and ADHD medication adherence. A few studies found that child comorbid conditions, especially ODD, mediate poor ADHD medication adherence, possibly secondary to an increased caregiver-child conflict.^30,53,54 However, other studies have reported that the presence of comorbid ODD, depression, and anxiety predicted increased adherence to ADHD medications.^37,46

Medication-related factors

Adverse effects of medications are the most commonly cited reason for ADHD medication nonadherence.^5,33,54-56 The adverse effects most often linked to nonadherence are reduced weight/appetite, increased aggressive behavior/irritability, and sleep difficulties.^54,57 Studies comparing methylphenidates and amphetamines, including 2 recent meta-analyses, suggest that amphetamines may be less well-tolerated on average, particularly with regard to emotional lability and irritability.^45,58,59 Therefore, clinicians might consider using methylphenidate-based preparations as first-line psychopharmacologic interventions in children with ADHD, as is consistent with the findings and conclusions drawn by a recent systematic review and meta-analysis of the comparative efficacy and tolerability of ADHD medications.⁶⁰

On the other hand, increased ADHD medication effectiveness has been associated with improved medication adherence.^5,34,54-56 Medication titration and dosing factors have also been shown to affect adherence. Specifically, adherence has been improved when ADHD medications are titrated in a systematic manner soon after starting treatment, and when families have an early first contact with a physician after starting medication (within 3 months).²⁸ In addition, use of a simplified dose regimen has been linked to better adherence: patients who are prescribed long-acting stimulants are more likely to adhere to treatment compared with patients who take short-acting formulations.^{26,40,49,61-63} It is possible that long-acting stimulants increase adherence because they produce more even and sustained effects on ADHD symptoms throughout the day, compared with short-acting formulations.⁶⁴ Furthermore, the inconvenience of taking multiple doses throughout the day, as well as the potential social stigma of mid-school day dosing, may negatively impact adherence to short-acting formulations.¹⁰

Continue to: Health care/system factors

Several studies have investigated the influence of health services factors on ADHD medication adherence. Specifically, limited transportation services and lack of mental health providers in the community have been linked to decreased ADHD medication adherence.^47,65,66 Furthermore, limited insurance coverage and higher costs of ADHD medications, which lead to substantial out-of-pocket payments for families, have been associated with decreased likelihood of ADHD medication adherence.^29,67

Clinician-related factors also can affect ADHD medication adherence. For example, a clinician’s lack knowledge of ADHD care can negatively impact ADHD medication adherence.⁶⁸ Two studies have documented improved ADHD medication adherence when treatment is provided by specialists (eg, child psychiatrists) rather than by community primary care providers, possibly because specialists are more likely to provide close stimulant titration and monitoring (ie, ≥ 3 visits in the first 90 days) and use higher maximum doses.^62,69 Furthermore, ADHD medication initiation and adherence are increased when patients have a strong working alliance with their clinician and trust the health care system,^31,34,35 as well as when there is a match between the caregiver’s and clinician’s perception of the cause, course, and best treatment practices for a child’s ADHD.⁶⁵

Strategies to improve medication adherence

A number of strategies to improve ADHD medication adherence can be derived from our knowledge of the factors that influence adherence.

Patient/family education. Unanswered questions about ADHD diagnosis, etiology, and medication adverse effects can negatively impact the ADHD treatment process. Therefore, patient/family education regarding ADHD and its management is necessary to improve medication adherence, because it helps families attain the knowledge, confidence, and motivation to manage their child’s condition.

Clinicians have an important role in educating patients about⁷⁰:

• the medications they are taking
• why they are taking them
• what the medications look like
• the time of medication administration
• the potential adverse effects
• what to do if adverse effects occur
• what regular testing/monitoring is necessary.

Clinicians can provide appropriate psychoeducation by sharing written materials and trusted websites with families (see Related Resources).

Behavioral strategies. Behavioral interventions have been among the most effective strategies for improving medication adherence in other chronic conditions.⁷¹ Behavioral strategies are likely to be particularly important for families of children with ADHD and comorbid conditions such as ODD because these families experience considerable caregiver-child conflict.⁷² Moreover, parents of children with ADHD are at higher risk for having ADHD and depression themselves,⁷³ both of which may interfere with a parent’s ability to obtain and administer medications consistently. Thus, for these families, using a combination of psychoeducation and behavioral strategies will be necessary to affect change in attitude and behavior. Behavioral strategies that can be used to improve medication adherence include:

• Technology-based interventions can reduce the impact of environmental barriers to adherence. For example, pharmacy automatic prescription renewal systems can reduce the likelihood of families failing to obtain ADHD medication refills. Pill reminder boxes, smartphone alerts, and setting various alarms can effectively prompt caregivers/patients to administer medication. In particular, these methods can be crucial in families for which multiple members have ADHD and its attendant difficulties with organization and task completion.
• Caregiver training may assist families in developing specific behavioral management skills that support adherence. This training can be as straightforward as instructing caregivers on the use of positive reinforcement when teaching their children to swallow pills. It may also encompass structured behavioral interventions aimed at training caregivers to utilize rewards and consequences in order to maximize medication adherence.⁷⁴

Continue to: Clinician interventions

Clinician interventions. Clinicians can use decision aids to help inform families about treatment options, promote shared decision making, and decrease uncertainty about the treatment plan⁷⁵ (see Related Resources). Early titration of ADHD medications and early first contact (within months of starting medication treatment) between caregivers and clinicians, whether via in-person visit, telephone, or email, have also been related to improved adherence.²⁸ Furthermore, clinicians can improve adherence by prescribing a simplified medication regimen (ie, long-acting formulations that provide full-day coverage). To address the negative impact of high out-of-pocket ADHD medication costs on adherence, clinicians can also prescribe generic preparations and/or “preferred” medications options on an individual patient’s formulary.

Because clinician knowledge and expertise in ADHD care has been linked to improved patient medication adherence,⁶⁸ clinicians are encouraged to use the American Academy of Pediatrics (AAP) guideline for diagnosis and treatment of ADHD, which includes a supplemental process of care algorithm (last published in 2011,¹⁰ with an updated guideline anticipated in 2019), as well as the AAP/National Institute for Children’s Health Quality (NICHQ) ADHD Toolkit,⁷⁶ which includes items helpful for ADHD diagnosis and treatment. The Society for Developmental and Behavioral Pediatrics is also developing a clinical practice guideline for the diagnosis and treatment of complex ADHD (ie, ADHD complicated by coexisting mental health, developmental, and/or psychosocial conditions or issues), with publication anticipated in 2019. Primary care providers can also improve their expertise in ADHD care by pursuing additional mental health–related trainings (such as those conducted by the REACH Institute).⁷⁷

Because receiving ADHD care from a specialist has been shown to improve medication initiation and adherence,^62,69 other strategies to address the short supply of child psychiatrists include offering incentives to medical students to pursue a career in child psychiatry (eg, loan forgiveness). Telepsychiatry and co-location of mental health specialists and primary care providers are additional innovative ways in which ADHD specialty care can be delivered to more patients.⁶⁴

Finally, providing culturally-sensitive care can strengthen the clinician-caregiver relationship and promote adherence to treatment. For example, clinicians can partner with local groups to increase their understanding of how different racial/ethnic groups perceive ADHD and its treatment.⁶⁴

Peer support models. Peers are credible role models who have a valued role in facilitating the use of mental health services by empowering families and enhancing service satisfaction.⁷⁸ In several communities in the United States, peer models using family advocates have been introduced.⁷⁹ Family advocates are typically caregivers of children who have special needs or have been involved in the mental health system. Their perspective—as peers and first-hand consumers of the health care and/or mental health system—can make them powerful and effective coaches to families of children with ADHD. By helping families to navigate ADHD care systems successfully, family advocates can play an important role in enhancing ADHD medication adherence, although further investigation is needed. In addition, the stigma around ADHD medication use, which adversely impacts adherence, can be mitigated if caregivers participate in organized ADHD-related support groups (eg, Children and Adults with ADHD [CHADD]).

Continue to: Health disparity-reducing interventions

Health disparity-reducing interventions. Successful health disparity-reducing interventions—such as those developed to enhance care of other chronic disorders including asthma and diabetes—can be applied to improve ADHD care. These interventions, which include medical-legal partnerships (eg, between clinicians, social workers, legal advocates, and community partners) in primary care centers, have been shown to improve health insurance coverage and therefore health care access.^80,81 Although some hardships linked to nonadherence (eg, low socioeconomic status) may not be amenable to health care–related interventions, screening for these hardships can identify children who are most at risk for poor adherence. This would alert clinicians to proactively identify barriers to adherence and implement mitigation strategies. This might include developing more streamlined, easier-to-follow management plans for these patients, such as those that can be delivered through pharmacist-physician collaborative programs⁸² and school-based therapy programs.^83-85

Bottom Line

Suboptimal adherence to medications for attention-deficit/hyperactivity disorder (ADHD) can be addressed through patient/family education, behavioral strategies, clinician interventions, peer support models, and health disparity-reducing interventions. By improving ADHD treatment adherence, these interventions have the potential to maximize long-term outcomes.

Related Resources

• Cohen Children’s Medical Center Northwell Health. The ADHD Medication Guide. www.ADHDMedicationGuide.com. Revised December 31, 2017.
• Cincinnati Children’s Hospital Medical Center. Decision aids to facilitate shared decision making in practice. www.cincinnatichildrens.org/service/j/anderson-center/ evidence-based-care/decision-aids.
• CHADD. Children and Adults with attention-deficit/ hyperactivity disorder. www.chadd.org.

Drug Brand Name

Methylphenidate • Concerta, Ritalin

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, affecting 8% to 12% of school-aged children in the United States^1-3 with significant impairments that often persist into adulthood.^4-8 Current guidelines recommend stimulant medication and/or behavioral therapies as first-line treatments for ADHD.^9,10 There is a wealth of evidence on the efficacy of stimulants in ADHD, with the most significant effects noted on core ADHD symptoms.^11,12 Additional evidence links stimulants to decreased long-term negative outcomes, including reduced school absences and grade retention,¹³ as well as modestly but significantly improved reading and math scores.¹⁴ Other studies have reported that individuals with ADHD who receive medication have decreased criminality,^15,16 motor vehicle accidents,^17,18 injuries,¹⁹ substance abuse,^20-22 and risk for subsequent and concurrent depression.²³ Therefore, the evidence suggests that consistent medication treatment helps improve outcomes for individuals with ADHD.

Adherence is defined as “the extent to which a person’s behavior (eg, taking medication) corresponds with agreed recommendations from a clinician.”²⁴ Unfortunately, pediatric ADHD medication adherence has been found to be poor (approximately 64%).^25-30 Nonadherence to ADHD medication has been linked to multiple factors, including caregiver/family and child/adolescent factors (Table 1), medication-related factors (Table 2), and health care/system factors (Table 3). Understanding and addressing these factors is essential to maximizing long-term outcomes. In this article, we review the factors associated with nonadherence to ADHD medication, and outline strategies to improve adherence.

Caregiver/family characteristics

Caregiver beliefs about ADHD and their attitudes toward treatment have been associated with the initiation of and adherence to ADHD medication. For example, caregivers who view a child’s difficulties as a medical disorder that requires a biologic intervention are more likely to accept and adhere to medication.³¹ Similarly, caregivers who perceive ADHD medication as safe, effective, and socially acceptable are more likely to be treatment-adherent.^32-35Other caregiver-related factors associated with improved ADHD medication adherence include:

• increased caregiver knowledge about ADHD³³
• receiving an ADHD diagnosis based on a thorough diagnostic process (ie, comprehensive psychological testing)³⁶
• satisfaction with information about medicine
• comfort with the treatment plan.³⁴

Socioeconomic status, family functioning, and caregiver mental health diagnoses (eg, ADHD, depression) have also been linked to ADHD medication adherence. Several studies, including the Multimodal Treatment Study of Children with ADHD,¹¹ a landmark study of stimulant medication for children with ADHD, have found an association between low income and decreased likelihood of receiving ADHD medication.^2,37-39 Further, Gau et al⁴⁰ found that negative caregiver-child relationships and family dysfunction were associated with poor medication adherence in children with ADHD.⁹ Prior studies have also shown that mothers of children with ADHD are more likely to have depression and/or anxiety,^41,42 and that caregivers with a history of mental health diagnoses are more accepting of initiating medication treatment for their children.⁴³ However, additional studies have found that caregiver mental health diagnoses decreased the likelihood of ADHD medication adherence.^40,44

Child characteristics

Child characteristics associated with decreased ADHD medication adherence include older age (eg, adolescents vs school-aged children),^{29,30,34,40,45-47} non-White race, Hispanic ethnicity,^29,33,48-51 female gender,^29,33,52 lower baseline ADHD symptom severity,^30,37 and child unwillingness to take medications.³⁴ However, prior studies have not been completely consistent about the relationship between child comorbid conditions (eg, oppositional defiant disorder [ODD], conduct disorder) and ADHD medication adherence. A few studies found that child comorbid conditions, especially ODD, mediate poor ADHD medication adherence, possibly secondary to an increased caregiver-child conflict.^30,53,54 However, other studies have reported that the presence of comorbid ODD, depression, and anxiety predicted increased adherence to ADHD medications.^37,46

Medication-related factors

Adverse effects of medications are the most commonly cited reason for ADHD medication nonadherence.^5,33,54-56 The adverse effects most often linked to nonadherence are reduced weight/appetite, increased aggressive behavior/irritability, and sleep difficulties.^54,57 Studies comparing methylphenidates and amphetamines, including 2 recent meta-analyses, suggest that amphetamines may be less well-tolerated on average, particularly with regard to emotional lability and irritability.^45,58,59 Therefore, clinicians might consider using methylphenidate-based preparations as first-line psychopharmacologic interventions in children with ADHD, as is consistent with the findings and conclusions drawn by a recent systematic review and meta-analysis of the comparative efficacy and tolerability of ADHD medications.⁶⁰

On the other hand, increased ADHD medication effectiveness has been associated with improved medication adherence.^5,34,54-56 Medication titration and dosing factors have also been shown to affect adherence. Specifically, adherence has been improved when ADHD medications are titrated in a systematic manner soon after starting treatment, and when families have an early first contact with a physician after starting medication (within 3 months).²⁸ In addition, use of a simplified dose regimen has been linked to better adherence: patients who are prescribed long-acting stimulants are more likely to adhere to treatment compared with patients who take short-acting formulations.^{26,40,49,61-63} It is possible that long-acting stimulants increase adherence because they produce more even and sustained effects on ADHD symptoms throughout the day, compared with short-acting formulations.⁶⁴ Furthermore, the inconvenience of taking multiple doses throughout the day, as well as the potential social stigma of mid-school day dosing, may negatively impact adherence to short-acting formulations.¹⁰

Continue to: Health care/system factors

Several studies have investigated the influence of health services factors on ADHD medication adherence. Specifically, limited transportation services and lack of mental health providers in the community have been linked to decreased ADHD medication adherence.^47,65,66 Furthermore, limited insurance coverage and higher costs of ADHD medications, which lead to substantial out-of-pocket payments for families, have been associated with decreased likelihood of ADHD medication adherence.^29,67

Clinician-related factors also can affect ADHD medication adherence. For example, a clinician’s lack knowledge of ADHD care can negatively impact ADHD medication adherence.⁶⁸ Two studies have documented improved ADHD medication adherence when treatment is provided by specialists (eg, child psychiatrists) rather than by community primary care providers, possibly because specialists are more likely to provide close stimulant titration and monitoring (ie, ≥ 3 visits in the first 90 days) and use higher maximum doses.^62,69 Furthermore, ADHD medication initiation and adherence are increased when patients have a strong working alliance with their clinician and trust the health care system,^31,34,35 as well as when there is a match between the caregiver’s and clinician’s perception of the cause, course, and best treatment practices for a child’s ADHD.⁶⁵

Strategies to improve medication adherence

A number of strategies to improve ADHD medication adherence can be derived from our knowledge of the factors that influence adherence.

Patient/family education. Unanswered questions about ADHD diagnosis, etiology, and medication adverse effects can negatively impact the ADHD treatment process. Therefore, patient/family education regarding ADHD and its management is necessary to improve medication adherence, because it helps families attain the knowledge, confidence, and motivation to manage their child’s condition.

Clinicians have an important role in educating patients about⁷⁰:

• the medications they are taking
• why they are taking them
• what the medications look like
• the time of medication administration
• the potential adverse effects
• what to do if adverse effects occur
• what regular testing/monitoring is necessary.

Clinicians can provide appropriate psychoeducation by sharing written materials and trusted websites with families (see Related Resources).

Behavioral strategies. Behavioral interventions have been among the most effective strategies for improving medication adherence in other chronic conditions.⁷¹ Behavioral strategies are likely to be particularly important for families of children with ADHD and comorbid conditions such as ODD because these families experience considerable caregiver-child conflict.⁷² Moreover, parents of children with ADHD are at higher risk for having ADHD and depression themselves,⁷³ both of which may interfere with a parent’s ability to obtain and administer medications consistently. Thus, for these families, using a combination of psychoeducation and behavioral strategies will be necessary to affect change in attitude and behavior. Behavioral strategies that can be used to improve medication adherence include:

• Technology-based interventions can reduce the impact of environmental barriers to adherence. For example, pharmacy automatic prescription renewal systems can reduce the likelihood of families failing to obtain ADHD medication refills. Pill reminder boxes, smartphone alerts, and setting various alarms can effectively prompt caregivers/patients to administer medication. In particular, these methods can be crucial in families for which multiple members have ADHD and its attendant difficulties with organization and task completion.
• Caregiver training may assist families in developing specific behavioral management skills that support adherence. This training can be as straightforward as instructing caregivers on the use of positive reinforcement when teaching their children to swallow pills. It may also encompass structured behavioral interventions aimed at training caregivers to utilize rewards and consequences in order to maximize medication adherence.⁷⁴

Continue to: Clinician interventions

Clinician interventions. Clinicians can use decision aids to help inform families about treatment options, promote shared decision making, and decrease uncertainty about the treatment plan⁷⁵ (see Related Resources). Early titration of ADHD medications and early first contact (within months of starting medication treatment) between caregivers and clinicians, whether via in-person visit, telephone, or email, have also been related to improved adherence.²⁸ Furthermore, clinicians can improve adherence by prescribing a simplified medication regimen (ie, long-acting formulations that provide full-day coverage). To address the negative impact of high out-of-pocket ADHD medication costs on adherence, clinicians can also prescribe generic preparations and/or “preferred” medications options on an individual patient’s formulary.

Because clinician knowledge and expertise in ADHD care has been linked to improved patient medication adherence,⁶⁸ clinicians are encouraged to use the American Academy of Pediatrics (AAP) guideline for diagnosis and treatment of ADHD, which includes a supplemental process of care algorithm (last published in 2011,¹⁰ with an updated guideline anticipated in 2019), as well as the AAP/National Institute for Children’s Health Quality (NICHQ) ADHD Toolkit,⁷⁶ which includes items helpful for ADHD diagnosis and treatment. The Society for Developmental and Behavioral Pediatrics is also developing a clinical practice guideline for the diagnosis and treatment of complex ADHD (ie, ADHD complicated by coexisting mental health, developmental, and/or psychosocial conditions or issues), with publication anticipated in 2019. Primary care providers can also improve their expertise in ADHD care by pursuing additional mental health–related trainings (such as those conducted by the REACH Institute).⁷⁷

Because receiving ADHD care from a specialist has been shown to improve medication initiation and adherence,^62,69 other strategies to address the short supply of child psychiatrists include offering incentives to medical students to pursue a career in child psychiatry (eg, loan forgiveness). Telepsychiatry and co-location of mental health specialists and primary care providers are additional innovative ways in which ADHD specialty care can be delivered to more patients.⁶⁴

Finally, providing culturally-sensitive care can strengthen the clinician-caregiver relationship and promote adherence to treatment. For example, clinicians can partner with local groups to increase their understanding of how different racial/ethnic groups perceive ADHD and its treatment.⁶⁴

Peer support models. Peers are credible role models who have a valued role in facilitating the use of mental health services by empowering families and enhancing service satisfaction.⁷⁸ In several communities in the United States, peer models using family advocates have been introduced.⁷⁹ Family advocates are typically caregivers of children who have special needs or have been involved in the mental health system. Their perspective—as peers and first-hand consumers of the health care and/or mental health system—can make them powerful and effective coaches to families of children with ADHD. By helping families to navigate ADHD care systems successfully, family advocates can play an important role in enhancing ADHD medication adherence, although further investigation is needed. In addition, the stigma around ADHD medication use, which adversely impacts adherence, can be mitigated if caregivers participate in organized ADHD-related support groups (eg, Children and Adults with ADHD [CHADD]).

Continue to: Health disparity-reducing interventions

Health disparity-reducing interventions. Successful health disparity-reducing interventions—such as those developed to enhance care of other chronic disorders including asthma and diabetes—can be applied to improve ADHD care. These interventions, which include medical-legal partnerships (eg, between clinicians, social workers, legal advocates, and community partners) in primary care centers, have been shown to improve health insurance coverage and therefore health care access.^80,81 Although some hardships linked to nonadherence (eg, low socioeconomic status) may not be amenable to health care–related interventions, screening for these hardships can identify children who are most at risk for poor adherence. This would alert clinicians to proactively identify barriers to adherence and implement mitigation strategies. This might include developing more streamlined, easier-to-follow management plans for these patients, such as those that can be delivered through pharmacist-physician collaborative programs⁸² and school-based therapy programs.^83-85

Bottom Line

Suboptimal adherence to medications for attention-deficit/hyperactivity disorder (ADHD) can be addressed through patient/family education, behavioral strategies, clinician interventions, peer support models, and health disparity-reducing interventions. By improving ADHD treatment adherence, these interventions have the potential to maximize long-term outcomes.

Related Resources

• Cohen Children’s Medical Center Northwell Health. The ADHD Medication Guide. www.ADHDMedicationGuide.com. Revised December 31, 2017.
• Cincinnati Children’s Hospital Medical Center. Decision aids to facilitate shared decision making in practice. www.cincinnatichildrens.org/service/j/anderson-center/ evidence-based-care/decision-aids.
• CHADD. Children and Adults with attention-deficit/ hyperactivity disorder. www.chadd.org.

Drug Brand Name

Methylphenidate • Concerta, Ritalin

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.