Download Treating Patient With Complicated ADHD

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
INTRODUCTION
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 COMPLICATED BY PSYCHIATRIC COMORBIDITIES
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 and aggression
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
ADHD and anxiety
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.
ADHD and depression
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.
ADHD and other comorbidities
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.
ADHD and learning disorders
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
ADHD and substance abuse
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.
ADHD and tourette syndrome or other tic disorders
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
ADHD and sleep or arousal problems
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
ADHD and bipolar disorder
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
CONCLUSION
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.
REFERENCES
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of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc
Psychiatry. 2006;45(6):642-57.
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.
3. Brown RT, Amler RW, Freeman WS, et al. Treatment of attention-deficit/hyperactivity disorder: overview
of the evidence. Pediatrics. 2005;115(6):e749-57.
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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 attentiondeficit/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.
Lina Cassandra Vawter, MD
PGY 2
Psychiatry
University of Massachusetts Memorial Health Care
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Caroline Fisher, MD, PhD
Associate Director
Psychiatric Education and Training
Assistant Professor of Psychiatry
Consulting Staff, Pediatric Neurology
Department of Psychiatry
University of Massachusetts Medical School
Medical Director and Co-owner
Pediatric Behavioral Health LLC