Sergio V. Delgado, MD

Treatment-resistant OCD can be a debilitating condition. Diagnostic clarity is crucial to fully elicit symptoms and identify comorbid conditions in order to develop practical, evidence-based treatment strategies and improve the patient’s and family’s quality of life. In this article, we delineate first-line strategies for treatment-resistant OCD and then review augmentation strategies, with an emphasis on glutamate-modulating agents.

Making the diagnosis

The diagnosis of OCD is made when a patient meets DSM-5 criteria for the presence of obsessions and/or compulsions, which are defined as unwanted, distressing, intrusive, recurrent thoughts or images (obsessions) and repetitive behaviors or mental acts (compulsions).¹ OCD is considered a chronic waxing and waning disorder; stress and lack of sleep lead to worsening symptoms. The hidden nature of symptoms and the reinforcement provided by the reduction in anxiety after performing a compulsion contribute to sustained illness. Eliciting symptoms from patients may be challenging due to the shame they may feel. When reviewing symptoms on the Y-BOCS, it is helpful to preface questions with statements such as “Many people report excessive concern or disgust with…” to help the patient feel understood and less anxious, rather than using direct queries, such as “Are you bothered by…?”

Consider comorbid conditions

After making the initial diagnosis of OCD, it is important to assess whether the symptoms are better accounted for by another condition, and whether comorbid conditions are present (Table 1).

CASE CONTINUED
Ruling out other diagnoses

_

Initial treatment: CBT

Cognitive-behavioral therapy with exposures and response prevention (from here on referred to as CBT) has been established as a first-line, evidence-based treatment for OCD in both children and adults.^2,3 For patients with treatment-resistant OCD, intensive daily CBT in a partial hospitalization or inpatient setting that is a tailor-made, patient-specific program is one of the most effective treatments, with response rates of up to 70%^4-8 CBT’s advantages over medication include lower relapse rates and no known adverse effects. Unfortunately, CBT is underused^9-11 due in part to a shortage of trained clinicians, and because patients may favor the ease of taking medication over the time, effort, and cost involved in CBT.

First-line pharmacologic options for treating OCD are SSRIs and clomipramine, as supported by multiple randomized controlled trials (RCTs), meta-analyses, expert guidelines, and consensus statements (Table 2^2,12-14). No significant difference has been found among SSRIs for the treatment of OCD in a review of 17 studies that included more than 3,000 patients.¹⁵ Treatment with SSRIs or clomipramine is effective for 50% to 60% of patients.¹⁶ Many clinicians view the combination of an SSRI and CBT as the treatment of choice for OCD.²

Continue to: Reluctance to engage in CBT

To determine the next course of action, you review Mr. S’s treatment history. He has received adequate doses of 2 SSRIs and currently is taking clomipramine, 100 mg twice daily. He recently began CBT, which includes homework to help face his fears; however, Mr. S is reluctant to complete the exposure assignments, and after pausing for a few seconds as he tries to resist sending an apology email to his coworkers, he then returns to his compulsive behavior.

Facing treatment resistance

Although currently there isn’t a cure to resolve all traces of OCD, the goal of treatment is to decrease distress, interference, and the frequency of symptoms to a minimal level such that only the patients themselves are aware of symptoms. In broad terms, “response” has been defined as a decrease in symptoms, and “remission” has been defined as minimal symptoms after treatment.

Close to half of adults treated for OCD respond well to standard-of-care treatment (CBT and/or an SSRI), while the other 50% are considered partial responders or nonresponders.² For patients with OCD, researchers often define “treatment response” as a ≥25% reduction in symptom severity score on the Y-BOCS. Approximately 30% of adults with OCD do not respond substantially to the first-line treatments, and even those who are defined as “responders” in research studies typically continue to have significant symptoms that impact their quality of life.² In children, a clinical definition for treatment-refractory OCD has been presented as failing to achieve adequate symptom relief despite receiving an adequate course of CBT and at least 2 adequate trials of an SSRI or clomipramine.¹⁷ In the Pediatric OCD Treatment Study (POTS) trial, >46% of youth did not achieve remission from their OCD symptoms, even after receiving evidence-based care provided by experienced clinicians (combined treatment with CBT and an SSRI).¹⁸

_

Challenges in psychotherapy

Compassion is a key element in developing rapport with patients to help them face increasingly more challenging exposures. Making OCD the problem, not the person, is an essential element in helping patients move forward. Some clinicians may become frustrated with patients when treatment is not moving along well, referring to resistance, denial, or sabotage. According to March and Mulle,¹⁹ these terms lack the recognition and compassion that exposures are inherently difficult.¹⁹

Another challenge for therapists is if the patient’s presenting symptoms are personally offensive or a sensitive topic. For example, a therapist who is disgusted by public restrooms will find it difficult to tolerate the risks associated with exposure to germs and support a patient in touching objects in the restroom. Therapists also may be challenged when the patient’s fears align with the therapist’s religious beliefs. In these situations, consider transferring care to another therapist.

Family members need to learn about the nature of the illness and their roles in helping patients improve. Family members may unknowingly enable symptoms or criticize patients for their lack of motivation, which can lead to conflict in the home. Family dysfunction can in turn worsen OCD symptoms.

The most likely cause of lack of response to therapy is inexpert CBT.¹⁹ Deep breathing and relaxation training have been used as an active placebo in studies²⁰; in a meta-analysis examining the effective components of CBT, studies that added relaxation training were not more effective than those that employed exposures alone.²¹ Patients receiving CBT should be able to articulate the hierarchical approach used to gradually face their fears.

Continue to: Pharmacologic augmentation strategies

Pharmacologic augmentation strategies

Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains. In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d²² and with escitalopram after an increase of dose up to 50 mg/d.²³ However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.²⁴ A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.²⁵ As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.²⁶

Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment. Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.²⁷ On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.²⁸ To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.^29-31

Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),³² they have not been shown to be effective for OCD³³ or as augmentation to an SSRI.³⁴

N-acetylcysteine (NAC). Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.^35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.³⁷ No follow-up information is available, however.

In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.³⁸ However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.³⁹

Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.^40-43 A small study suggests that patients with OCD may be more likely to respond to memantine than patients with generalized anxiety disorder.⁴⁴ Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.⁴⁵

Continue to: Topiramate

Topiramate. Three 12-week RCTs examined topiramate augmentation at 100 to 400 mg/d in patients with OCD who had failed at least 1 previous trial of an SSRI. The earliest study was most encouraging: Y-BOCS scores decreased by 32% in the topiramate group but by only 2.4% in the placebo group.⁴⁶ However, the other 2 studies found no difference in the final OCD symptom severity score between active treatment and placebo groups,^47,48 and the use of topiramate, particularly at higher doses, was limited by its adverse effects.

Lamotrigine. Initially, lamotrigine augmentation of SSRIs in OCD did not appear to be helpful.⁴⁹ More recently, several case studies reported that lamotrigine, 100 to 200 mg/d, added to paroxetine or clomipramine, resulted in dramatic improvement in Y-BOCS scores for patients with long-standing refractory symptoms.^50,51 In a retrospective review of 22 patients who received augmentation with lamotrigine, 150 mg/d, 20 had a significant response; the mean decrease in Y-BOCS score was 67%.⁵² Finally, in a 16-week RCT, lamotrigine, 100 mg/d, added to an SSRI led to a significant decrease in both Y-BOCS score and depressive symptoms while also improving semantic fluency.⁵³

Ketamine. Ketamine is drawing increased attention for its nearly instantaneous antidepressant effect that lasts for up to 2 weeks after a single infusion.⁵⁴ In a study of 15 medication-free adults with continuous intrusive obsessions, 4 of 8 patients who received a single IV infusion of ketamine, 0.5 mg/kg, met the criteria for treatment response (>35% reduction in Y-BOCS score measured 1 week later); none of the patients who received a placebo infusion of saline met this criteria.⁵⁵ A small open-label trial of 10 treatment-refractory patients found that an infusion of ketamine, 0.5 mg/kg, was beneficial for comorbid depression but had only a minimal effect on OCD symptoms measured 3 days post-infusion.⁵⁶ A short-term follow-up on these patients revealed dysphoria in some responders.⁵⁷

D-cycloserine. The idea of using a pharmacologic agent to increase the speed or efficacy of behavioral therapy is intriguing. Proof of concept was demonstrated in a study that found that giving D-cycloserine prior to computerized exposure therapy significantly improved clinical response in patients with acrophobia.⁵⁸ However, using this approach to treating OCD netted mixed results; D-cycloserine was found to be most helpful during early stages of treatment.^59,60

Table 3 outlines the mechanisms of action and common uses for NAC, memantine, ketamine, topiramate, lamotrigine, and D-cycloserine. Table 4 summarizes the literature on the efficacy of some of the augmentation strategies for treating OCD described in this article.

Continue to: Alternative strategies

Augmentation strategies with neuroleptics,⁶¹ transcranial magnetic stimulation,⁶² and deep brain stimulation⁶³ have recently been reviewed. Space limitations preclude a comprehensive review of these strategies, but in a cross-sectional study of augmentation strategies in OCD, no difference was found in terms of symptom severity between those prescribed SSRI monotherapy or augmentation with neuroleptics, benzodiazepines, or antidepressants.⁶⁴

CASE CONTINUED
Progress in CBT

Mr. S agrees to a trial of NAC as an augmentation strategy, but after 8 weeks of treatment with NAC, 600 mg twice daily, his Y-BOCS had declined by only 2 points. He also complains of nausea and does not want to increase the dose. You discontinue NAC and opt to further explore his reaction to CBT. Mr. S shares that he has been seeing his psychologist only once every 3 weeks because he does not want to miss work. You encourage him to increase to weekly CBT sessions, and you obtain his permission to contact his therapist and his family members. Fortunately, his therapist is highly qualified, but unfortunately, Mr. S’s father has been sending him multiple critical emails about not advancing at his job and for being “lazy” at work. You schedule a session with Mr. S and his father. Great progress is made after Mr. S and his father both share their frustrations and come to understand and appreciate each other’s struggles. Four weeks later, after weekly CBT appointments, Mr. S has a Y-BOCS of 18 and spends <2 hours/d checking emails for errors and apologizing.

Bottom Line

It is unrealistic to expect OCD symptoms to be cured. Many ‘treatment-resistant’ patients have not received properly delivered cognitive-behavioral therapy, and this first-line treatment modality should be considered in every eligible patient, and augmented with a selective serotonin reuptake inhibitor (SSRI) when needed. Glutamatergic agents, in turn, can augment SSRIs.

Related Resources

• Yale-Brown Obsessive-Compulsive Scale. https://iocdf.org/ wp-content/uploads/2014/08/Assessment-Tools.pdf.
• The International OCD Foundation. https://iocdf.org.

Drug Brand Names
Citalopram • Celexa
Clomipramine • Anafranil
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Ketamine • Ketalar
Lamotrigine • Lamictal
Memantine • Namenda
Paroxetine • Paxil
Sertraline • Zoloft
Topiramate • Topomax

Treatment-resistant OCD can be a debilitating condition. Diagnostic clarity is crucial to fully elicit symptoms and identify comorbid conditions in order to develop practical, evidence-based treatment strategies and improve the patient’s and family’s quality of life. In this article, we delineate first-line strategies for treatment-resistant OCD and then review augmentation strategies, with an emphasis on glutamate-modulating agents.

Making the diagnosis

The diagnosis of OCD is made when a patient meets DSM-5 criteria for the presence of obsessions and/or compulsions, which are defined as unwanted, distressing, intrusive, recurrent thoughts or images (obsessions) and repetitive behaviors or mental acts (compulsions).¹ OCD is considered a chronic waxing and waning disorder; stress and lack of sleep lead to worsening symptoms. The hidden nature of symptoms and the reinforcement provided by the reduction in anxiety after performing a compulsion contribute to sustained illness. Eliciting symptoms from patients may be challenging due to the shame they may feel. When reviewing symptoms on the Y-BOCS, it is helpful to preface questions with statements such as “Many people report excessive concern or disgust with…” to help the patient feel understood and less anxious, rather than using direct queries, such as “Are you bothered by…?”

Consider comorbid conditions

After making the initial diagnosis of OCD, it is important to assess whether the symptoms are better accounted for by another condition, and whether comorbid conditions are present (Table 1).

CASE CONTINUED
Ruling out other diagnoses

_

Initial treatment: CBT

Cognitive-behavioral therapy with exposures and response prevention (from here on referred to as CBT) has been established as a first-line, evidence-based treatment for OCD in both children and adults.^2,3 For patients with treatment-resistant OCD, intensive daily CBT in a partial hospitalization or inpatient setting that is a tailor-made, patient-specific program is one of the most effective treatments, with response rates of up to 70%^4-8 CBT’s advantages over medication include lower relapse rates and no known adverse effects. Unfortunately, CBT is underused^9-11 due in part to a shortage of trained clinicians, and because patients may favor the ease of taking medication over the time, effort, and cost involved in CBT.

First-line pharmacologic options for treating OCD are SSRIs and clomipramine, as supported by multiple randomized controlled trials (RCTs), meta-analyses, expert guidelines, and consensus statements (Table 2^2,12-14). No significant difference has been found among SSRIs for the treatment of OCD in a review of 17 studies that included more than 3,000 patients.¹⁵ Treatment with SSRIs or clomipramine is effective for 50% to 60% of patients.¹⁶ Many clinicians view the combination of an SSRI and CBT as the treatment of choice for OCD.²

Continue to: Reluctance to engage in CBT

To determine the next course of action, you review Mr. S’s treatment history. He has received adequate doses of 2 SSRIs and currently is taking clomipramine, 100 mg twice daily. He recently began CBT, which includes homework to help face his fears; however, Mr. S is reluctant to complete the exposure assignments, and after pausing for a few seconds as he tries to resist sending an apology email to his coworkers, he then returns to his compulsive behavior.

Facing treatment resistance

Although currently there isn’t a cure to resolve all traces of OCD, the goal of treatment is to decrease distress, interference, and the frequency of symptoms to a minimal level such that only the patients themselves are aware of symptoms. In broad terms, “response” has been defined as a decrease in symptoms, and “remission” has been defined as minimal symptoms after treatment.

Close to half of adults treated for OCD respond well to standard-of-care treatment (CBT and/or an SSRI), while the other 50% are considered partial responders or nonresponders.² For patients with OCD, researchers often define “treatment response” as a ≥25% reduction in symptom severity score on the Y-BOCS. Approximately 30% of adults with OCD do not respond substantially to the first-line treatments, and even those who are defined as “responders” in research studies typically continue to have significant symptoms that impact their quality of life.² In children, a clinical definition for treatment-refractory OCD has been presented as failing to achieve adequate symptom relief despite receiving an adequate course of CBT and at least 2 adequate trials of an SSRI or clomipramine.¹⁷ In the Pediatric OCD Treatment Study (POTS) trial, >46% of youth did not achieve remission from their OCD symptoms, even after receiving evidence-based care provided by experienced clinicians (combined treatment with CBT and an SSRI).¹⁸

_

Challenges in psychotherapy

Compassion is a key element in developing rapport with patients to help them face increasingly more challenging exposures. Making OCD the problem, not the person, is an essential element in helping patients move forward. Some clinicians may become frustrated with patients when treatment is not moving along well, referring to resistance, denial, or sabotage. According to March and Mulle,¹⁹ these terms lack the recognition and compassion that exposures are inherently difficult.¹⁹

Another challenge for therapists is if the patient’s presenting symptoms are personally offensive or a sensitive topic. For example, a therapist who is disgusted by public restrooms will find it difficult to tolerate the risks associated with exposure to germs and support a patient in touching objects in the restroom. Therapists also may be challenged when the patient’s fears align with the therapist’s religious beliefs. In these situations, consider transferring care to another therapist.

Family members need to learn about the nature of the illness and their roles in helping patients improve. Family members may unknowingly enable symptoms or criticize patients for their lack of motivation, which can lead to conflict in the home. Family dysfunction can in turn worsen OCD symptoms.

The most likely cause of lack of response to therapy is inexpert CBT.¹⁹ Deep breathing and relaxation training have been used as an active placebo in studies²⁰; in a meta-analysis examining the effective components of CBT, studies that added relaxation training were not more effective than those that employed exposures alone.²¹ Patients receiving CBT should be able to articulate the hierarchical approach used to gradually face their fears.

Continue to: Pharmacologic augmentation strategies

Pharmacologic augmentation strategies

Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains. In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d²² and with escitalopram after an increase of dose up to 50 mg/d.²³ However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.²⁴ A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.²⁵ As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.²⁶

Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment. Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.²⁷ On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.²⁸ To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.^29-31

Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),³² they have not been shown to be effective for OCD³³ or as augmentation to an SSRI.³⁴

N-acetylcysteine (NAC). Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.^35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.³⁷ No follow-up information is available, however.

In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.³⁸ However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.³⁹

Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.^40-43 A small study suggests that patients with OCD may be more likely to respond to memantine than patients with generalized anxiety disorder.⁴⁴ Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.⁴⁵

Continue to: Topiramate

Topiramate. Three 12-week RCTs examined topiramate augmentation at 100 to 400 mg/d in patients with OCD who had failed at least 1 previous trial of an SSRI. The earliest study was most encouraging: Y-BOCS scores decreased by 32% in the topiramate group but by only 2.4% in the placebo group.⁴⁶ However, the other 2 studies found no difference in the final OCD symptom severity score between active treatment and placebo groups,^47,48 and the use of topiramate, particularly at higher doses, was limited by its adverse effects.

Lamotrigine. Initially, lamotrigine augmentation of SSRIs in OCD did not appear to be helpful.⁴⁹ More recently, several case studies reported that lamotrigine, 100 to 200 mg/d, added to paroxetine or clomipramine, resulted in dramatic improvement in Y-BOCS scores for patients with long-standing refractory symptoms.^50,51 In a retrospective review of 22 patients who received augmentation with lamotrigine, 150 mg/d, 20 had a significant response; the mean decrease in Y-BOCS score was 67%.⁵² Finally, in a 16-week RCT, lamotrigine, 100 mg/d, added to an SSRI led to a significant decrease in both Y-BOCS score and depressive symptoms while also improving semantic fluency.⁵³

Ketamine. Ketamine is drawing increased attention for its nearly instantaneous antidepressant effect that lasts for up to 2 weeks after a single infusion.⁵⁴ In a study of 15 medication-free adults with continuous intrusive obsessions, 4 of 8 patients who received a single IV infusion of ketamine, 0.5 mg/kg, met the criteria for treatment response (>35% reduction in Y-BOCS score measured 1 week later); none of the patients who received a placebo infusion of saline met this criteria.⁵⁵ A small open-label trial of 10 treatment-refractory patients found that an infusion of ketamine, 0.5 mg/kg, was beneficial for comorbid depression but had only a minimal effect on OCD symptoms measured 3 days post-infusion.⁵⁶ A short-term follow-up on these patients revealed dysphoria in some responders.⁵⁷

D-cycloserine. The idea of using a pharmacologic agent to increase the speed or efficacy of behavioral therapy is intriguing. Proof of concept was demonstrated in a study that found that giving D-cycloserine prior to computerized exposure therapy significantly improved clinical response in patients with acrophobia.⁵⁸ However, using this approach to treating OCD netted mixed results; D-cycloserine was found to be most helpful during early stages of treatment.^59,60

Table 3 outlines the mechanisms of action and common uses for NAC, memantine, ketamine, topiramate, lamotrigine, and D-cycloserine. Table 4 summarizes the literature on the efficacy of some of the augmentation strategies for treating OCD described in this article.

Continue to: Alternative strategies

Augmentation strategies with neuroleptics,⁶¹ transcranial magnetic stimulation,⁶² and deep brain stimulation⁶³ have recently been reviewed. Space limitations preclude a comprehensive review of these strategies, but in a cross-sectional study of augmentation strategies in OCD, no difference was found in terms of symptom severity between those prescribed SSRI monotherapy or augmentation with neuroleptics, benzodiazepines, or antidepressants.⁶⁴

CASE CONTINUED
Progress in CBT

Mr. S agrees to a trial of NAC as an augmentation strategy, but after 8 weeks of treatment with NAC, 600 mg twice daily, his Y-BOCS had declined by only 2 points. He also complains of nausea and does not want to increase the dose. You discontinue NAC and opt to further explore his reaction to CBT. Mr. S shares that he has been seeing his psychologist only once every 3 weeks because he does not want to miss work. You encourage him to increase to weekly CBT sessions, and you obtain his permission to contact his therapist and his family members. Fortunately, his therapist is highly qualified, but unfortunately, Mr. S’s father has been sending him multiple critical emails about not advancing at his job and for being “lazy” at work. You schedule a session with Mr. S and his father. Great progress is made after Mr. S and his father both share their frustrations and come to understand and appreciate each other’s struggles. Four weeks later, after weekly CBT appointments, Mr. S has a Y-BOCS of 18 and spends <2 hours/d checking emails for errors and apologizing.

Bottom Line

It is unrealistic to expect OCD symptoms to be cured. Many ‘treatment-resistant’ patients have not received properly delivered cognitive-behavioral therapy, and this first-line treatment modality should be considered in every eligible patient, and augmented with a selective serotonin reuptake inhibitor (SSRI) when needed. Glutamatergic agents, in turn, can augment SSRIs.

Related Resources

• Yale-Brown Obsessive-Compulsive Scale. https://iocdf.org/ wp-content/uploads/2014/08/Assessment-Tools.pdf.
• The International OCD Foundation. https://iocdf.org.

Drug Brand Names
Citalopram • Celexa
Clomipramine • Anafranil
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Ketamine • Ketalar
Lamotrigine • Lamictal
Memantine • Namenda
Paroxetine • Paxil
Sertraline • Zoloft
Topiramate • Topomax

Treatment-resistant OCD can be a debilitating condition. Diagnostic clarity is crucial to fully elicit symptoms and identify comorbid conditions in order to develop practical, evidence-based treatment strategies and improve the patient’s and family’s quality of life. In this article, we delineate first-line strategies for treatment-resistant OCD and then review augmentation strategies, with an emphasis on glutamate-modulating agents.

Making the diagnosis

The diagnosis of OCD is made when a patient meets DSM-5 criteria for the presence of obsessions and/or compulsions, which are defined as unwanted, distressing, intrusive, recurrent thoughts or images (obsessions) and repetitive behaviors or mental acts (compulsions).¹ OCD is considered a chronic waxing and waning disorder; stress and lack of sleep lead to worsening symptoms. The hidden nature of symptoms and the reinforcement provided by the reduction in anxiety after performing a compulsion contribute to sustained illness. Eliciting symptoms from patients may be challenging due to the shame they may feel. When reviewing symptoms on the Y-BOCS, it is helpful to preface questions with statements such as “Many people report excessive concern or disgust with…” to help the patient feel understood and less anxious, rather than using direct queries, such as “Are you bothered by…?”

Consider comorbid conditions

After making the initial diagnosis of OCD, it is important to assess whether the symptoms are better accounted for by another condition, and whether comorbid conditions are present (Table 1).

CASE CONTINUED
Ruling out other diagnoses

_

Initial treatment: CBT

Cognitive-behavioral therapy with exposures and response prevention (from here on referred to as CBT) has been established as a first-line, evidence-based treatment for OCD in both children and adults.^2,3 For patients with treatment-resistant OCD, intensive daily CBT in a partial hospitalization or inpatient setting that is a tailor-made, patient-specific program is one of the most effective treatments, with response rates of up to 70%^4-8 CBT’s advantages over medication include lower relapse rates and no known adverse effects. Unfortunately, CBT is underused^9-11 due in part to a shortage of trained clinicians, and because patients may favor the ease of taking medication over the time, effort, and cost involved in CBT.

First-line pharmacologic options for treating OCD are SSRIs and clomipramine, as supported by multiple randomized controlled trials (RCTs), meta-analyses, expert guidelines, and consensus statements (Table 2^2,12-14). No significant difference has been found among SSRIs for the treatment of OCD in a review of 17 studies that included more than 3,000 patients.¹⁵ Treatment with SSRIs or clomipramine is effective for 50% to 60% of patients.¹⁶ Many clinicians view the combination of an SSRI and CBT as the treatment of choice for OCD.²

Continue to: Reluctance to engage in CBT

To determine the next course of action, you review Mr. S’s treatment history. He has received adequate doses of 2 SSRIs and currently is taking clomipramine, 100 mg twice daily. He recently began CBT, which includes homework to help face his fears; however, Mr. S is reluctant to complete the exposure assignments, and after pausing for a few seconds as he tries to resist sending an apology email to his coworkers, he then returns to his compulsive behavior.

Facing treatment resistance

Although currently there isn’t a cure to resolve all traces of OCD, the goal of treatment is to decrease distress, interference, and the frequency of symptoms to a minimal level such that only the patients themselves are aware of symptoms. In broad terms, “response” has been defined as a decrease in symptoms, and “remission” has been defined as minimal symptoms after treatment.

Close to half of adults treated for OCD respond well to standard-of-care treatment (CBT and/or an SSRI), while the other 50% are considered partial responders or nonresponders.² For patients with OCD, researchers often define “treatment response” as a ≥25% reduction in symptom severity score on the Y-BOCS. Approximately 30% of adults with OCD do not respond substantially to the first-line treatments, and even those who are defined as “responders” in research studies typically continue to have significant symptoms that impact their quality of life.² In children, a clinical definition for treatment-refractory OCD has been presented as failing to achieve adequate symptom relief despite receiving an adequate course of CBT and at least 2 adequate trials of an SSRI or clomipramine.¹⁷ In the Pediatric OCD Treatment Study (POTS) trial, >46% of youth did not achieve remission from their OCD symptoms, even after receiving evidence-based care provided by experienced clinicians (combined treatment with CBT and an SSRI).¹⁸

_

Challenges in psychotherapy

Compassion is a key element in developing rapport with patients to help them face increasingly more challenging exposures. Making OCD the problem, not the person, is an essential element in helping patients move forward. Some clinicians may become frustrated with patients when treatment is not moving along well, referring to resistance, denial, or sabotage. According to March and Mulle,¹⁹ these terms lack the recognition and compassion that exposures are inherently difficult.¹⁹

Another challenge for therapists is if the patient’s presenting symptoms are personally offensive or a sensitive topic. For example, a therapist who is disgusted by public restrooms will find it difficult to tolerate the risks associated with exposure to germs and support a patient in touching objects in the restroom. Therapists also may be challenged when the patient’s fears align with the therapist’s religious beliefs. In these situations, consider transferring care to another therapist.

Family members need to learn about the nature of the illness and their roles in helping patients improve. Family members may unknowingly enable symptoms or criticize patients for their lack of motivation, which can lead to conflict in the home. Family dysfunction can in turn worsen OCD symptoms.

The most likely cause of lack of response to therapy is inexpert CBT.¹⁹ Deep breathing and relaxation training have been used as an active placebo in studies²⁰; in a meta-analysis examining the effective components of CBT, studies that added relaxation training were not more effective than those that employed exposures alone.²¹ Patients receiving CBT should be able to articulate the hierarchical approach used to gradually face their fears.

Continue to: Pharmacologic augmentation strategies

Pharmacologic augmentation strategies

Selective serotonin reuptake inhibitors. While most OCD research trials have assessed SSRIs in 12-week studies, clinicians may consider extending SSRI treatment for an additional 12 weeks for nonresponders because some patients will continue to make gains. In the past, it was generally believed that higher doses of SSRIs are needed for treating OCD than for treating major depressive disorder. For instance, greater improvement was seen with 250 to 400 mg/d of sertraline compared with 200 mg/d²² and with escitalopram after an increase of dose up to 50 mg/d.²³ However, more recently, this notion of higher doses being necessary for treatment response has been called into question. For example, a study of escitalopram found similar responses to 10 mg/d vs 20 mg/d after 24 weeks.²⁴ A meta-analysis of adult studies of SSRIs for OCD supported higher doses as being more effective, but noted that the drop-out rate from treatment was greater in patients treated with higher doses.²⁵ As a note of caution, long-term, high-dose maintenance therapy increases the risk of adverse reactions.²⁶

Following a failed treatment with a first SSRI, it remains debatable as to what ought to be the second pharmacologic treatment. Although clomipramine is often reserved for treatment after 2 failed trials of an SSRI due to its greater risk of adverse effects, in an open-label study, switching from an SSRI to clomipramine led to greater response than switching from one SSRI to another.²⁷ On the other hand, while meta-analyses have reported greater treatment effect for oral clomipramine than for SSRIs, direct head-to-head comparisons have not supported this notion.²⁸ To get the best of both worlds, some clinicians employ a strategy of combining clomipramine with an SSRI, while monitoring for adverse effects and interactions such as serotonin syndrome.^29-31

Benzodiazepines. Although benzodiazepines are useful for brief treatment of an anxiety disorder (eg, for a person with a fear of heights who needs to take an airplane),³² they have not been shown to be effective for OCD³³ or as augmentation to an SSRI.³⁴

N-acetylcysteine (NAC). Two RCTs of adults with OCD who received adjunctive NAC, 3 g/d in divided doses, found no significant difference in the treatment arms by the conclusion of 16 weeks—either both groups improved, or both groups failed to improve.^35,36 In a 10-week study of patients with moderate to severe OCD symptoms, NAC, 2 g/d, as augmentation to fluvoxamine, 200 mg/d, showed a significant time x interaction in the treatment group.³⁷ No follow-up information is available, however.

In a multicenter RCT of NAC given to children and adolescents with OCD as augmentation to citalopram, symptoms decreased and the quality-of-life score improved, with a large treatment effect size in the NAC group.³⁸ However, in a study aimed at examining NAC in youth with Tourette syndrome, OCD symptoms were measured as a secondary outcome and there was no benefit of NAC over placebo.³⁹

Memantine. Four 8- to 12-week RCTs in adults with OCD favored adjunctive memantine, 20 mg/d, taken with an SSRI, over placebo.^40-43 A small study suggests that patients with OCD may be more likely to respond to memantine than patients with generalized anxiety disorder.⁴⁴ Case reports have noted that memantine has been beneficial for pediatric patients with refractory OCD.⁴⁵

Continue to: Topiramate

Topiramate. Three 12-week RCTs examined topiramate augmentation at 100 to 400 mg/d in patients with OCD who had failed at least 1 previous trial of an SSRI. The earliest study was most encouraging: Y-BOCS scores decreased by 32% in the topiramate group but by only 2.4% in the placebo group.⁴⁶ However, the other 2 studies found no difference in the final OCD symptom severity score between active treatment and placebo groups,^47,48 and the use of topiramate, particularly at higher doses, was limited by its adverse effects.

Lamotrigine. Initially, lamotrigine augmentation of SSRIs in OCD did not appear to be helpful.⁴⁹ More recently, several case studies reported that lamotrigine, 100 to 200 mg/d, added to paroxetine or clomipramine, resulted in dramatic improvement in Y-BOCS scores for patients with long-standing refractory symptoms.^50,51 In a retrospective review of 22 patients who received augmentation with lamotrigine, 150 mg/d, 20 had a significant response; the mean decrease in Y-BOCS score was 67%.⁵² Finally, in a 16-week RCT, lamotrigine, 100 mg/d, added to an SSRI led to a significant decrease in both Y-BOCS score and depressive symptoms while also improving semantic fluency.⁵³

Ketamine. Ketamine is drawing increased attention for its nearly instantaneous antidepressant effect that lasts for up to 2 weeks after a single infusion.⁵⁴ In a study of 15 medication-free adults with continuous intrusive obsessions, 4 of 8 patients who received a single IV infusion of ketamine, 0.5 mg/kg, met the criteria for treatment response (>35% reduction in Y-BOCS score measured 1 week later); none of the patients who received a placebo infusion of saline met this criteria.⁵⁵ A small open-label trial of 10 treatment-refractory patients found that an infusion of ketamine, 0.5 mg/kg, was beneficial for comorbid depression but had only a minimal effect on OCD symptoms measured 3 days post-infusion.⁵⁶ A short-term follow-up on these patients revealed dysphoria in some responders.⁵⁷

D-cycloserine. The idea of using a pharmacologic agent to increase the speed or efficacy of behavioral therapy is intriguing. Proof of concept was demonstrated in a study that found that giving D-cycloserine prior to computerized exposure therapy significantly improved clinical response in patients with acrophobia.⁵⁸ However, using this approach to treating OCD netted mixed results; D-cycloserine was found to be most helpful during early stages of treatment.^59,60

Table 3 outlines the mechanisms of action and common uses for NAC, memantine, ketamine, topiramate, lamotrigine, and D-cycloserine. Table 4 summarizes the literature on the efficacy of some of the augmentation strategies for treating OCD described in this article.

Continue to: Alternative strategies

Augmentation strategies with neuroleptics,⁶¹ transcranial magnetic stimulation,⁶² and deep brain stimulation⁶³ have recently been reviewed. Space limitations preclude a comprehensive review of these strategies, but in a cross-sectional study of augmentation strategies in OCD, no difference was found in terms of symptom severity between those prescribed SSRI monotherapy or augmentation with neuroleptics, benzodiazepines, or antidepressants.⁶⁴

CASE CONTINUED
Progress in CBT

Mr. S agrees to a trial of NAC as an augmentation strategy, but after 8 weeks of treatment with NAC, 600 mg twice daily, his Y-BOCS had declined by only 2 points. He also complains of nausea and does not want to increase the dose. You discontinue NAC and opt to further explore his reaction to CBT. Mr. S shares that he has been seeing his psychologist only once every 3 weeks because he does not want to miss work. You encourage him to increase to weekly CBT sessions, and you obtain his permission to contact his therapist and his family members. Fortunately, his therapist is highly qualified, but unfortunately, Mr. S’s father has been sending him multiple critical emails about not advancing at his job and for being “lazy” at work. You schedule a session with Mr. S and his father. Great progress is made after Mr. S and his father both share their frustrations and come to understand and appreciate each other’s struggles. Four weeks later, after weekly CBT appointments, Mr. S has a Y-BOCS of 18 and spends <2 hours/d checking emails for errors and apologizing.

Bottom Line

It is unrealistic to expect OCD symptoms to be cured. Many ‘treatment-resistant’ patients have not received properly delivered cognitive-behavioral therapy, and this first-line treatment modality should be considered in every eligible patient, and augmented with a selective serotonin reuptake inhibitor (SSRI) when needed. Glutamatergic agents, in turn, can augment SSRIs.

Related Resources

• Yale-Brown Obsessive-Compulsive Scale. https://iocdf.org/ wp-content/uploads/2014/08/Assessment-Tools.pdf.
• The International OCD Foundation. https://iocdf.org.

Drug Brand Names
Citalopram • Celexa
Clomipramine • Anafranil
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Ketamine • Ketalar
Lamotrigine • Lamictal
Memantine • Namenda
Paroxetine • Paxil
Sertraline • Zoloft
Topiramate • Topomax

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.