Attention-Deficit/Hyperactivity Disorder Newsletter Series 1, Issue 2, 2007

TREATING PATIENTS WITH COMPLICATED ADHD

Lina Cassandra Vawter, MD
University of Massachusetts Memorial Health Care

Caroline Fisher, MD, PhD
University of Massachusetts Medical School

According to parental surveys, nearly 8% of children in the United States have been diagnosed with attention-deficit/hyperactivity disorder (ADHD) at some point during their childhood. Slightly over half of these children have taken medications for the condition, with boys outnumbering girls at a ratio of more than 2:1. Approximately one third of children with ADHD outgrow the disorder; an estimated 4.4% of adults have ADHD. Significant morbidity and mortality is associated with ADHD in children with the condition, which leads to an increased likelihood of failure in school and an increased chance of use or abuse of illicit substances. The symptoms of ADHD are also associated with numerous other undesirable social and injury-related statistics, such as an increased number of speeding tickets, more vehicular crashes, more license suspensions, and fewer friends.

Countless theories abound regarding the pathogenesis of ADHD, ranging from an association with the genetics of dopamine-mediated neural pathways to the supposition of a cause and effect relationship with extensive television viewing. Family, twin, and adoption data support the theory that ADHD is heritable, with more than twenty different genes having been studied to date. Current pharmacologic treatment strategies, however, base their therapeutic principles on empirical studies of the cerebral spinal fluid (CSF) in affected individuals. Such studies have demonstrated depletions of dopamine and norepinephrine in the nucleus accumbens and locus coeruleus, respectively. Mild cases of ADHD may respond to environmental restructuring and behavioral therapy. Very young children are often treated with these nonpharmacologic therapies before the demands of school become more strenuous.

Stimulants are the first line of treatment and are considered the most effective therapy.¹ Stimulant drugs currently in use (eg, methylphenidate [MPH], amphetamine [AMP]) act within the dopaminergic system. The results of the Multimodal Treatment Study of ADHD have suggested a linear relationship between stimulant dose and clinical response, though each patient has his or her own dose-response curve. Additionally, longer-acting formulations of stimulants are now available, such as dextromethylphenidate. These newer, longer-acting stimulants are associated with less diversion for abuse, greater persistence, and reduced stimulant switching.² Atomoxetine, a norepinephrine reuptake inhibitor, has proven effectiveness and has replaced pemoline for treatment of refractory symptoms. Bupropion or a tricyclic antidepressant can also be added to further treat refractory symptoms in ADHD.³

While evidence that polypharmacy generally offers an advantage over stimulants alone is not available, patients with comorbidities may be helped by the addition of other classes of medication.

ADHD is commonly complicated by several different psychiatric conditions. The discussion to follow reviews 3 psychiatric comorbidities that are common in patients with ADHD and the evidence-based treatments for these conditions when they appear concomitantly with ADHD.

ADHD may be accompanied by aggressive behavior that ranges from stealing or fighting to severe aggressive outbursts. In these cases, ADHD can commonly be associated with anxiety, depression, or both. Aggression is of obvious concern to caregivers and anyone else exposed to the behavior. Aggressive behaviors should be quantified using one of many available rating scales that include instruments for both caregivers and clinicians. Specific different diagnoses may accompany the aggression, such as oppositional defiant disorder or intermittent explosive disorder. Irrespective of the exact categorization of the behavior and diagnosis, the aggressive behavior can be targeted and reduced.

Treatment begins with standard ADHD treatments. Pharmacologically, this means starting with MPH or AMP. After initiation of standard therapy, the aggression should be reassessed. If treatment elicits improvement of the ADHD symptoms but the aggression is unsatisfactorily improved, a behavioral intervention should be carried out next. This intervention should target the aggressive behavior and contributing factors, such as family or social contacts.

If attenuation of the aggression is unsuccessful after the initiation of standard pharmacologic therapy for ADHD and behavioral interventions, or if the aggression is considered a danger to the patient or others, an atypical antipsychotic should be added to the initial stimulant. Of the atypical antipsychotics, risperidone has been studied most often in randomized controlled trials, but any atypical antipsychotic may be tried. The patient and his or her family should be counseled on the risks associated with atypical antipsychotic treatment, such as extrapyramidal symptoms and gastrointestinal adverse effects.⁴ If the aggression still does not abate with the addition of atypical antipsychotics, a trial of divalproex sodium or lithium is recommended. Some evidence also suggests efficacy of clonidine in treatment of comorbid aggression with ADHD.⁵

Comorbidity rates for ADHD and anxiety are estimated at 20-45%. Levy postulates that comorbidity of ADHD and anxiety is related to a deficit in the synaptic gating mechanism between the prefrontal cortex, hippocampus, and amygdala.⁶ At the level of the nucleus accumbens, this synapse is impaired by decreased prefrontal cortex inhibition, which allows anxiety-related processes greater impact as a result of greater influence by the amygdala. This damaged “gating of anxiety” at the accumbens allows increased amygdala-based fear or anxiety to manifest in some children with ADHD.⁶

Atomoxetine was initially developed for depression but was observed to be effective in treating ADHD and, as some literature suggests, in treating anxiety. Its adverse effect profile is very similar to that of the stimulants, with the notable exceptions that atomoxetine does not worsen anxiety or reduce growth rates. It is recommended as an alternative initial therapy to address ADHD, especially when associated with anxiety. This recommendation complements previously recommended treatments, specifically therapy that starts with stimulants and adds selective serotonin reuptake inhibitors (SSRIs) for refractory anxiety.

In effect, the treatment of coexisting ADHD and anxiety has 3 optional initial treatment strategies: atomoxetine, stimulants such as MPH or AMP, and nonpharmacologic alternatives. If atomoxetine is used as a first trial with subsequent failure to improve symptoms, stimulants should be tried next. On the other hand, if stimulants are the first class of medications initiated, and the symptoms of ADHD improve but the symptoms of anxiety worsen or do not improve for the patient, an SSRI should be added. If neither ADHD nor anxiety responds to stimulants, atomoxetine should be tried.⁷ Indeed, these coexisting but separate disorders are just that and must often be treated separately.

In treating the patient with both ADHD and major depressive disorder (MDD), whichever disorder is the most severe and impairing should be treated first. Treatment of one of these coexisting disorders often results in improvement in or abatement of symptoms of the other.

The Children’s Medication Algorithm Project consensus conference held in June of 2007 updated recommendations for approaching the patient with coexisting MDD and ADHD. The conference reinforced the notion that the disorder with the most severe symptoms should be treated first. If monotherapy improves symptoms in one category but not the other, the next step in each separate algorithm should be followed.⁸ For example, if the treatment of MDD results in improvement of depression but not of the symptoms of ADHD, stimulant therapy may be added to antidepressant therapy. If, on the other hand, ADHD treatment is initiated first with stimulants or atomoxetine, and depression does not improve, cognitive behavioral therapy, SSRIs, or both may be added to stimulant treatment.⁹

The 2 conditions are assessed separately between regimen changes, and treatment is augmented or altered, as needed. For depression, this may mean starting with monotherapy with an SSRI, cognitive behavioral therapy (CBT), or both, followed by a change in SSRI monotherapy, if needed. If only a partial response is elicited, this treatment can be augmented with lithium, bupropion, or mirtazapine. An alternative to augmenting the SSRI is to discontinue the SSRI and instead treat with monotherapy of a drug from a different class (eg, venlafaxine, bupropion, mirtazapine, duloxetine). Evidence-based psychotherapy can be used at any time during treatment; CBT and interpersonal therapy have also demonstrated efficacy in clinical trials.

Several other comorbidities can occur with ADHD. Among these are learning disorders, substance abuse, Tourette syndrome or other tic disorders, sleep and arousal problems, and bipolar disorder.

Children with ADHD repeat grades more often, have lower grades, are more often placed in special classes, and need more tutoring than children without ADHD. Conservative estimates of the prevalence of learning disorders among children with ADHD are about 20-25%.¹⁰ One randomized placebo-controlled trial suggested that children with learning disabilities tended to respond more poorly to treatment with MPH than did children without learning disabilities (55% vs 75 %). This was mainly because children with mathematics disabilities were particularly unresponsive.¹¹

Retrospective and prospective data demonstrate that children with ADHD are at increased risk for substance abuse. Current data suggest that these children become involved with cigarettes, alcohol, and then drugs. In addition, persons with ADHD, regardless of comorbidity, tend to remain addicted longer than peers without ADHD. However, research shows that children who are treated with stimulants for ADHD have lower rates of substance use disorders than those who are untreated.

Children with tic disorders frequently have comorbid ADHD. MPH or AMP is an appropriate first-line agent, as most patients do not experience increased tics with these medications. If tics worsen, whichever stimulant was not used initially should be tried sequentially. The addition of an alpha agonist is the next line of treatment. If response is insufficient, an atypical antipsychotic should be tried in its place. Finally, haloperidol or pimozide is added to the stimulant of choice.¹²

Parental-report studies demonstrate sleep problems in children with ADHD, though numerous objective studies have not indicated consistent concomitant differences in sleep architecture. Many sleep disturbances, such as restless sleep, night awakening, and difficulty with sleep latency, can be attributed to either medication effects or common psychiatric comorbidities. Many other sleep disorders, such as sleep-disordered breathing, restless legs syndrome, periodic limb movement disorder, delayed sleep phase syndrome, and narcolepsy, may also present concomitantly with the symptoms of ADHD. Evidence has linked the same neurotransmitters that regulate sleep and attention or arousal with ADHD; abnormalities in noradrenergic and dopaminergic systems may be found in both ADHD and sleep disorders.¹³

Since many features of ADHD and bipolar disorder overlap (eg, distractibility, inattention, impulsivity, hyperactivity), the rate of comorbidity of these two conditions may be overestimated. The misdiagnosis of bipolar disorder as ADHD can lead to inappropriate treatment resulting in mania or rapid cycling.¹⁴ In one study, however, in pediatric patients with both established ADHD and bipolar disorder, after the patients’ manic symptoms were controlled with valproic acid, a randomized placebo-controlled trial of AMP was undertaken. The trial demonstrated the combination of these two medications as both safe and effective treatment. Valproic acid alone did not effectively treat the symptoms of ADHD in these patients with concurrent bipolar disorder.¹⁵

ADHD is a common disorder in childhood, with a significant percentage of patients continuing to experience the symptoms of their ADHD into adulthood. The symptoms of ADHD often coexist with other psychiatric disorders, such as aggression, depression, and anxiety. Evidence-based treatments for these comorbidities are available, including both pharmacologic and nonpharmacologic therapy. In most cases, and especially when the patient has comorbid depression, treatment of the most debilitating condition should begin first. Symptoms should be reassessed at periodic intervals and after each regimen change.

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2. Connor DF, Glatt SJ, Lopez ID, Jackson D, Melloni RH Jr. Psychopharmacology and aggression. I: a meta-analysis of stimulant effects of overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry. 2002;41:253-61.

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4. Armenteros J, Lewis JE, Davalos M. Risperidone augmentation for treatment-resistant aggression in attention-deficit/hyperactivity disorder: a placebo-controlled pilot study. J Am Acad Child Adolesc Psychiatry. 2007;46(5):558-65.

5. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;42(8):886-94.

6. Levy F. Synaptic gating and ADHD: a biological theory of comorbidity of ADHD and anxiety. Neuropsychopharmacology. 2004;29:1589-96.

7. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2005;44:418-27.

8. Emslie GJ, Hughes CW, Crismon ML, et al. A feasibility study of the childhood depression medication algorithm: the Texas Children’s Medication Algorithm Project (CMAP). J Am Acad Child Adolesc Psychiatry. 2004; 43(5):519-27.

9. Kratochvil C, Newcorn JH, Arnold LE, et al. Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. J Am Acad Child Adolesc Psychiatry. 2005;44(9):915-24.

10. Spencer TJ, Biederman J, Mick E. Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol. 2007;32(6):631-42.

11. Grizenko N, Bhat M, Schwartz G, Ter-Stepanian M, Joober R. Efficacy of methylphenidate in children with attention-deficit hyperactivity disorder and learning disabilities: a randomized crossover trial. J Psychiatry Neurosci. 2006;31(1):46-51.

12. Millman RP, Working Group on Sleepiness in Adolescents/Young Adults, AAP Committee on Adolescence. Excessive sleepiness in adolescents and young adults: causes, consequences, and treatment strategies. Pediatrics. 2005;115(6):1774-86.

13. Krishnan K. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med. 2005;67:1-8.

14. Scheffer R, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry. 2005;162(1):58-64.