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Introduction

ADHD is categorized by the DSM-5 as a neurodevelopmental disorder; it is no longer grouped with ODD and conduct disorder under disruptive behavior disorders.

This article covers the general treatment guidelines, while properties of stimulants are covered here.

AACAP practice parameter recommendations are listed under corresponding headings.

Prevalence and Etiology

  • Prevalence of ADHD is 3-8% in the US depending on methodology and criteria used.
  • The prevalence in school-age children is 8-11%.
  • M:F ratio is 3:1 in general population; it is even higher in clinical samples and when only the "predominantly hyperactive" subtype is considered. Girls are more likely to have the inattentive subtype of ADHD. Girls are less likely than boys to have aggressive symptoms or the comorbidities of ODD and conduct disorder. (3)
  • 4% of adults have ADHD (DSM-5: 2.5%) with M:F ratio closer to 1:1. This is explained in part by the fact that the hyperactivity/impulsivity, more common in boys, tends to resolve with age, while symptoms of inattention persist into adulthood.
  • Heritability of ADHD is high - 60-76%.
  • Most common comorbidities are ODD (40-60%), conduct disorder, anxiety disorders, and learning disorders.

Imaging findings

  • Abnormalities in white matter linking lateral prefrontal cortex with head of caudate and anterior putamen are linked to deficits in executive functioning.
  • Abnormal processing of rewards is linked to dysfunction in the circuit spanning the ventral striatum (nucleus accumbens, ventral caudate, putamen) with the limbic system.
  • Reduced striatal volume, particularly in putamen and head of caudate, and reduced size of cerebellar vermis are most consistent findings.
  • Some recovery of normal basal ganglia structure takes place with stimulant treatment. (Sobel LJ., Am J Psychiatry 2010;167)
  • Functional neuroimaging reveals hypoperfusion in frontal, prefrontal and striatal areas.

Risk Factors

While highly heritable, ADHD has not only genetic, but also many environmental risk factors, which could play an influential role in emergence of ADHD. Early environmental factors are particularly important; these include prenatal, perinatal, and early post-natal factors.

  • Smoking during pregnancy is a well-established risk factor for ADHD.
  • Low birth weight and premature birth are other important risk factors.
  • Perinatal psychosocial factors include maternal depression, h/o paternal antisocial behaviors, nonintact family, and young maternal age. (4)

Evaluation

Making the diagnosis

  • Inquire about each of the 18 ADHD symptoms, specifically, the age of onset, severity, frequency, and duration. Various rating scales can speed up this process and should be a part of every ADHD evaluation, according to AACAP.(1)
  • Establish chronicity of symptoms, age of onset, and settings in which impairment occurs. While home and school are typically inquired about, asking about other settings where a degree of impulse control and focusing are expected, may be revealing (restaurant, supermarket, church).
  • DSM-5 requires that some of the symptoms are present before age of 12, which is loosening of the DSM-IV criteria.

Differential diagnosis

The differential diagnosis must be considered for all children presenting with attention and hyperactivity problems, and it includes the following important conditions:

  • lead exposure/toxicity
  • learning and language disorders
  • intellectual disability/MR/Fetal alcohol syndrome
  • developmental disorder
  • bipolar/mood disorder
  • hearing/vision problems
  • sensory processing disorders
  • absence and other seizures
  • drugs and medication side effects
  • head trauma
  • hyperthyroidism
  • trauma/neglect/reactive attachment disorder

Rating scales

These free instruments are helpful in making the diagnosis, as well as tracking progress over time.

  • Vanderbilt ADHD Diagnostic Rating Scale [1] is available in parent and teacher versions to help evaluate children 6-12yo.
  • SNAP-IV Rating Scale-Revised [2] can be filled out by parents or teachers; it's designed for youth 6-18, and includes symtpoms of ADHD, ODD and aggression.

Treatment

For preschoolers with mild or moderate symptoms of ADHD, parent training and behavioral modification is recommended as the initial treatment. For school-age children, stimulants are generally appropriate as the first-line treatment.

Stimulants

  • Stimulants are the most efficacious treatment for ADHD; this is addressed in a separate article.
  • Summaries of the landmark MTA study and the PATS trial can be found there as well.

Atomoxetine

  • Atomoxetine is a norepinephrine reuptake inhibitor (NRI), acting on presynaptic neurons with a half-life of 4 hours. (Desipramine, a TCA, is similarly an NRI, but is assoiacated with cardiac conduction problems)
  • Atomoxetine (Strattera) was initially developed as an antidepressant, but received FDA approval for ADHD (children 6yo and older). Its efficacy is less robust than stimulants'; it's considered a 2-nd line alternative.
  • Black box warnings on this drug include: hepatitis, increased aggression and hostility and suicidal thinking.
  • Atomoxetine (ATX) is metabolized by cyp450 2D6, with potential interactions with fluoxetine and paroxetine.
  • ATX had been studied in young children (5-6yo) in a RCT, n=101; after 8 weeks 40% of children on drug meet response criteria, vs. 22% on placebo; this difference was not statistically significant, but the drug was well-tolerated. (Kratochvil, 2011)
  • A comprehensive meta-analysis of placebo-controlled ATX trials (Schwartz S, Correll CU, JAACAP 2014), N=3928, revealed the following:
    • moderate effect size of at least 0.59 in total, inattentive, and hyperactive scores;
    • greater response rate to AMX compared to placebo, with NNT of 4;
    • "bimodal" response to AMX with 45% of youth improving by >40% but a 40% non-response rate (failure to improve >25%)
    • raters of adverse effects that lead to discontinuation of AMX were low but significantly higher than placebo's, particularly GI, and CNS-related side effects, as well as anorexia and fatigue, but not insomnia.
    • increase in heart rate on ATX was modest and more youth lost >5% of body weight (26% vs 2.4% on placebo), NNH=5.
    • rates of serious side effects (suicidality, aggression, depression) were not statistically different.
    • improvement in ODD symptoms was noted, and attributed to anti-ADHD properties of AMX, strengthening the recommendation to treat ADHD sxs before comorbid ODD.
  • ATX is particularly effective (and has fewer side effects than stimluants) in youth with comorbid ADHD and autism. (Arnold E JACAAP 2006)

α-2 agonisists

Clonidine binds α-2A, -2B, and -2C post-synaptic auto-receptors in the prefrontal cortex, while guanfacine selectively binds α-2A receptors;

  • immideate-release preparations are used off-label (only have FDA indication for hypertension),
  • extended-release preparations of clonidine and guanfacine are approved by the FDA for pediatric ADHD.
  • in a meta-analysis (Hirota, JACAAP 2014), monotherapy with α-2 agonists significantly reduced ADHD and ODD symtpoms.
    • effect size was moderate (0.56-0.59) for monotherapy, and smaller as an add-on treatment
    • α-2 agonists were not discontinued more than the placebo, but had more somnolence (NNH=4), fatigue (NNH=10) and sedation (NNH=17).
    • clonidine-IR was associated with bradycardia and hypotension, while gunafacine-XR was assoicated with QTC prolongation.

Guanfacine

Guanfacine, available in long-acting preparation Intiniv, is a specific α-2A agonist. Unlike stimulants, it lowers blood pressure, and does not cause sedation associated with clonidine. Its effects on ADHD symptoms is modest compared to stimulants. It can be used alone or to augment treatment with stimulants to decrease rebound, and improve sleep.

  • An trial of guanfacine extended-release as an add-on to a stimulant in chilren 7-17yo with partial, response to the stimulant, demonstrated guanfacine safety and efficasy as AM or PM dose. (Wilens TE, JAACAP 2012(1)).
  • It had shown fair results as solo treatment in children with comorbid Tourette's and ADHD.
  • A placebo-controlled trial of gianfacine XR as add-on to a stimulant in 6-17 y.o. ADHD children with partial response to psychostimulant monotherapy, demonstrated greater response and remission rates. This was true for either AM or PM administration of guanfacine.(Cutler, JAACAP 53:10, 2014)

Clonidine

  • Clonidine, a pre-synaptic α-2 agonist in the locus coeruleus (LC) where it reduces LC firing and inhibits norepinephrine (NE) release.
  • It provides modest efficacy in treatment of ADHD, and associated with sedation.
  • Abrupt withdrawal can cause rebound hypertension.

In the Treatment of ADHD in Children with Tourette's Syndrome (TACT) study of 136 children (age 7 to 14 years) with ADHD and a chronic tic disorder were randomized to one of four treatments: clonidine, methylphenidate, clonidine + methylphenidate, or placebo.

  • all treatment groups separated from placebo;
  • the CLO+MPH group did better than the individual drug groups in primary outcomes;
  • CLO+MPH group had less insomnia than MPH alone group, and less sedation than CLO alone group.
  • in the MPH alone group, methylphenidate frequently exacerbated tics.

Omega-3 fatty acids

A meta-analysis of ten trials (n=699), showed that omega-3 fatty acid supplementation, particularly Eicosapentaenoic acid demonstrated a small but significant effect in improving ADHD symptoms. (7)

Other medications

Wellbutrin has modest evidence for effectiveness in ADHD.

Modafinil was shown to be effective for ADHD in RCTs, but not approved due to risk of erythema multiforme.

Therapies

Medication is generally a first-line intervention as a part of multimodal approach to treatment of ADHD.

  • Behavioral therapies have been studied extensively, but a recent meta-analysis demonstrated significicant methodology shortcomings and only modest benefit on core symptoms of ADHD (8, meta-analysis).
  • However, behavioral therapies are effective in other areas of child and parent functioning, such as decreasing negative parenting, and decreasing children’s co-morbid conduct problems (9, meta-analysis)
  • Likewise, meta-analysis showed that cognitive training had limited effect on ADHD symptoms (Cortese S, JAACAP 2014)

Special Topics

ADHD and Epilepsy

  • Prevalence of epilepsy in children and adolescents is about 0.5-1%; these children are more likely to have ADHD than their peers without seizures. This is particularly relevant in children with absence seizures, in whom pharmacologic seizure control may not adequately restore attention.
  • Differentiating the symptoms is important in children with comorbid epilepsy and ADHD, as well as in children with staring episodes (partial complex or absence seizures); the inattention of ADHD will generally respond to touch and redirection, and children do not experience post-ictal drowsiness. EEG is sometimes necessary for diagnosis.
  • Further, children with ADHD are more likely to have subclinical/epileptiform EEG findings as compared to general population. While they are not considered to have seizures/epilepsy, periods of epileptiform changes are often associated with transient impairment of attention and cognition.
  • Antiepileptics and ADHD - Children with epilepsy may experience a sudden improvement in learning, attention, social, and behavior domains when their seizures are treated. This was termed the release phenomenon; it is unclear if this effect is due to seizure control or a separate effect of an antiepileptic. However, phenobarbital and topiramate may cause deterioration in attention and behavior.
  • ADHD Treatments and Seizures - It is unclear if stimulants lower seizure threshold; the concern is greater with methylphenidate-based stimulants. However, in children with epilepsy seizures frequency is not increased when methyphenidate is introduced.
    • Stimulants remain the treatment of choice in youth with moderate ADHD and well-controlled seizure disorder.
    • Bupropion had been found to cause an increase in seizure frequency in a dose dependent fashion (SR preparation is safer as it results in lower serum levels). (1)

ADHD and School

  • Having ADHD puts the child at risk for academic underachievement; 30% of children with ADHD have to repeat a grade. (3)
  • In many children with ADHD, the underachievement is significant enough to be considered a learning disorder. Learning disorder is a significant discrepancy between one's intelligence/IQ/general mental abilities and the performance in the specific academic area (math, reading, writing, etc.) ADHD and learning disability can coexist or be confused with one another.

ADHD and Depression

  • Youth with ADHD have a five-fold increased risk of having major depressive disorder, and are at higher risk of recurrence of a depressive episode
  • In youth with ADHD, diagnosis of MDD is complicated by the overlap of symptoms of the two conditions (difficulty concentrating) and side effects of stimulants (decreased sleep and appetite, dysphoria, and irritability).
    • Symptoms that may be helpful in diferentiating comorbid MDD include social withdrawal, anhedonia, depressive cognitions, suicidal thoughts, and psychomotor retardation. (W.B. Daviss 2008)
    • Careful screening for hypomania and bipolar disorder is important whenever any mood symspoms or side effects are considered.
  • While randomized controlled trials are lacking, monotherapy with bupropion, or combination therapies with stimulants and SSRIs or atomoxetine may be reasonable options.
  • Black-box warning outlining suicidality-related side effects of SSRI's AND atomoxetine must be considered.

CMAP Algorithm

A consensus statement from the experts in the Texas Children’s Medication Algorithm Project (CMAP) recommend targeting the more severe of the two comorbid conditions with monotherapy (stimulant or SSRI) first. AS with any treatment, close monitoring and psychoeducation are paramount.

  • If, after a trial of stimulant, depressive and ADHD symtpoms persist, the stimulant could be changed to an SSRI. Combination treatment should be considered if ADHD symtpoms have responded to the stimulant, but depression persisted.
  • If depression is judged to be more severe at outset, two SSRIs trials are justified before trying bupropion or TCA. Combination treatment (SSRI + stimulant) should be considered if youth's depression improved on SSRI but symptoms of ADHD persisted.(Pliszka et al. 2006; Hughes et al. 2007)

Sluggish Cognitive Tempo

Sluggish Cognitive Tempo is a cluster of symptoms, potentially a new psychiatric disorder, that is similar but distinct from inattentive ADHD.

  • The symptoms include being prone to daydreaming, difficulty staying alert when bored, easily confused, spacey or 'in a fog', lethargic or more tired than others, and processing information as quickly or as accurately as others.
  • According to a meta-analysis published in JACAAP (Becker S. et. al.), the concept has strong internal validity and there is preliminary support for the external validity of SCT; there is no clear way to capture SCT in diagnostic terms based on current evidence base.

ADHD and Substance Use

  • ADHD increases risk of future substance use, particularly nicotine use; Stimulants have protective effects if started prior to age 10.
  • The comorbidity of ADHD and substance use is addressed here.

Further Reading

(1) Schubert R. Attention Deficit Disorder and Epilepsy. Pediatric Neurology 2005;32:1-10.
(2) Practice Parameter, ADHD. JACAP, 46:7, Jul 2007
(3) Russell Barkley Attention-Deficit Hyperactivity Disorder. 2006
(4) Galera C. et.al. Early Risk Factors for Hyperactivity-Impulsivity and Inattention Trajectories From Age 17 Months to 8 Years Arch.Gen.Psych 68(12), Dec. 2011, 1267-75
(5)W.B.Daviss Review of Co-Morbid Depression in Pediatric ADHD: Etiologies, Phenomenology, and Treatment J of Child and Adol Psychopharmocology 18(6):565-71, 2008
(6) Hughes CW, Emslie GJ, Crismon ML, et al. Texas Children’s Medication Algorithm Project: Update from Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry 46:667–689, 2007.
(7) Bloch MH, Qawasmi A. Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology: systematic review and meta-analysis. JAACAP 2011 Oct;50(10):991-1000
(8)Sonuga-Barke E, Bret al. Non-pharmacological interventions for attention-deficit/hyperactivity disorder: systematic review and meta-analyses of randomised controlled trials of dietary and psychological treatments. Am J Psychiatry. 2013; 170:275-289
(9) Daley D. et.al. Behavioral interventions in attention-deficit/hyperactivity disorder: a meta-analysis of randomized controlled trials across multiple outcome domains. J Am Acad Child Adolesc Psychiatry. 2014 Aug;53(8):835-47, 847.e1-5.


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