What is ADD?What is ADD? A neurobehavioral disorder that begins in A neurobehavioral disorder that begins in

early childhood and can continue into early childhood and can continue into adulthoodadulthood

ADHD may be associated with long-term ADHD may be associated with long-term adverse outcomes:adverse outcomes:• Deficits in academic skillsDeficits in academic skills• Deficits in family/social skillsDeficits in family/social skills• Learning disabilitiesLearning disabilities

May be accompanied by internalizing May be accompanied by internalizing disorders (sadness, anxiety) as well as disorders (sadness, anxiety) as well as aggressive and oppositional disorders and aggressive and oppositional disorders and learning disabilitieslearning disabilities

ADHDADHD Attention deficit hyperactivity disorder as a Attention deficit hyperactivity disorder as a

diagnosis generates controversy.diagnosis generates controversy. It is both under & over diagnosed-some It is both under & over diagnosed-some

believe it does not exist.believe it does not exist. Epidemiological studies show 5-10% of school Epidemiological studies show 5-10% of school

age children may be classified with the age children may be classified with the disorder.disorder.

It is a complex neuro-developmental It is a complex neuro-developmental constellation of problems rather than a single constellation of problems rather than a single disorder.disorder.

Often associated with co-morbid conditions.Often associated with co-morbid conditions. No diagnostic test to confirm clinical diagnosisNo diagnostic test to confirm clinical diagnosis

1897 Kerr- Word blindness in smart children1897 Kerr- Word blindness in smart children 1937 Bradley- Benzedrine & Brain activity1937 Bradley- Benzedrine & Brain activity 1941 Bender -Minimal Brain & Hyperkinesis1941 Bender -Minimal Brain & Hyperkinesis 1947 Strauss-Brain damaged child syndrome1947 Strauss-Brain damaged child syndrome 1963 Connors/Eisenberg-Ritalin&Hyperkinesis1963 Connors/Eisenberg-Ritalin&Hyperkinesis 1968 DSM II Hyperactivity1968 DSM II Hyperactivity 1971 Wender -Minimal Brain Dysfunction1971 Wender -Minimal Brain Dysfunction 1987 DSM III Attention Deficit Disorder1987 DSM III Attention Deficit Disorder 1994 DSM IV Attention Deficit Hyperactivity 1994 DSM IV Attention Deficit Hyperactivity

Historical background

Published in 2001, an updated DSM-IV (DSM-IV-TR) remained essentially the same. In summary, the diagnostic criteria for ADHD include:

EITHER -- at least 6 symptoms of inattentiveness that have persisted for 6 months and are maladaptive (eg, "difficulty sustaining attention," "does not seem to listen," "easily

distracted," "loses...toys, school assignments")

OR -- at least 6 symptoms of hyperactivity (eg, "leaves seat in classroom", "runs about or climbs excessively", "talks excessively") and/or impulsivity (eg, "blurts out answers," "difficulty waiting turn," "interrupts or intrudes on others") that have

persisted for 6 months and are maladaptive

In addition, the symptoms needed to have been present before age 7, be expressed in at least two settings (DSM-III and DSM-IV mention work here), and demonstrate

clear evidence of impairment.

ADHDADHD

Legal StatusLegal Status Americans with Disabilities Act Americans with Disabilities Act

(ADA)(ADA) Rehabilitation Act of 1973Rehabilitation Act of 1973

ADHD EpidemiologyADHD Epidemiology

Most commonly diagnosed neurobehavioral Most commonly diagnosed neurobehavioral disorder in childrendisorder in children1, 21, 2

Symptoms typically appear between the ages Symptoms typically appear between the ages of 3 and 7 of 3 and 7

5%-10% of school-aged children may have 5%-10% of school-aged children may have ADHD; may bigherADHD; may bigher

Boys are diagnosed 4 to 9 times more often Boys are diagnosed 4 to 9 times more often than girlsthan girls44

In up to 60% of children, symptoms of ADHD In up to 60% of children, symptoms of ADHD continue into adulthoodcontinue into adulthood5-75-7

ADHDADHDGenetic StudiesGenetic Studies Strong familial association with increase first Strong familial association with increase first

degree relativesdegree relatives Monozygotic twin studies show 60-90% Monozygotic twin studies show 60-90%

concordance rate-concordance rate- Adoption/Consanguinity -positive correlationAdoption/Consanguinity -positive correlation

Specific GenesSpecific Genes Polygenetic disorder involving multiple genesPolygenetic disorder involving multiple genes Dopamine transporter gene DAT 1Dopamine transporter gene DAT 1 Dopamine receptor D4/Chromosome 3 ,5 ,11Dopamine receptor D4/Chromosome 3 ,5 ,11 ADHD/HKD polymorphisms on dopamine ADHD/HKD polymorphisms on dopamine

genesgenes

ADHDADHDLaboratory TestLaboratory Test No specific blood testNo specific blood test

HoweverHowever Lead level, CBC, EKG, Liver function Lead level, CBC, EKG, Liver function

may be indicated in certain cases.may be indicated in certain cases. Blood level of certain medication Blood level of certain medication

requiredrequired Toxicology screen in suspected cases Toxicology screen in suspected cases

of drug useof drug use EEG indicated for seizureEEG indicated for seizure

Recent FindingsRecent Findings Low birth weight, Fetal Alcohol syndromeLow birth weight, Fetal Alcohol syndrome Smoking during pregnancy + Alcohol,cocaineSmoking during pregnancy + Alcohol,cocaine Higher rates injury medical bills.Higher rates injury medical bills. Untreated leads to sociopathy -increase driving Untreated leads to sociopathy -increase driving

offenses, delinquency, school& work failure_offenses, delinquency, school& work failure_ Increased smoking & substance abuseIncreased smoking & substance abuse Multimodal Treatment study (MTA) 2001 Multimodal Treatment study (MTA) 2001

Closely monitored med. management more Closely monitored med. management more beneficial than intensive behavioral treatmentbeneficial than intensive behavioral treatment

Cross cultural validity- Dr..Bird-2000Cross cultural validity- Dr..Bird-2000

ADHDADHDGirlsGirls Girls show less hyperactivity than Girls show less hyperactivity than

boysboys Often Overwhelmed, disorganized & Often Overwhelmed, disorganized &

scatteredscattered Depression often coexists with ADHDDepression often coexists with ADHD Less potential for antisocial personality Less potential for antisocial personality

& substance abuse& substance abuse Tend to have higher rate of adolescent Tend to have higher rate of adolescent

pregnancy and substance abuse pregnancy and substance abuse compared to other females.compared to other females.

Similar neuro- anatomical substrateSimilar neuro- anatomical substrate

•Adolescents face increasing demands for planning, organizing, self control, and time management, thus requiring increased executive function. What appeared as hyperactivity in the younger child emerges as restlessness• In the adolescent. Poor organizational skills make high school and college years difficult for the adolescent and young adult with ADHD. Impairment follows and manifests as lower grades, more school suspensions, and higher college drop-out rates. •Furthermore, higher rates of illegal substance and alcohol use in adults with ADHD appear to have their beginnings in the adolescent years.

TESTINGTESTING

Tri –State AFF Rating Scale.Tri –State AFF Rating Scale.

Wechsler Intelligence Scale for Children (WISC-III)Wechsler Intelligence Scale for Children(WISC-R)Woodcock-Johnson Reading Mastery TestPeabody Individual Achievement TestPeabody Picture Vocabulary TestVineland Adaptive Behavior ScalesThematic Apperception Test (TAT).

Connors’ Parent &Teacher Rating Scale.

Psychological Testing

•For children with ADHD, academic difficulties are common. Among children with ADHD, prevalence of learning disabilities has not been well determined, with a wide range of reported levels from 9% to 94%.

• It is clear, that adults with ADHD have adaptive impairments relating to schooling in general. However, whether or not true learning disabilities remain an issue for adults with ADHD has not been determined. Conduct (20%) and oppositional-defiant (40%) disorders are commonly identified among children with ADHD.• •The prevalence of the disruptive behavior disorders decreases significantly beginning in adolescence and extending into adulthood; however, in adulthood, antisocial disorder is one of the comorbidities that can persist independently of continued ADHD symptoms.

DSM-VDSM-V®® Defines 3 ADHD Defines 3 ADHD SubtypesSubtypes

3 categories of ADHD (DSM-IV3 categories of ADHD (DSM-IV®® criteria)criteria)11 • Predominantly inattentive typePredominantly inattentive type• Predominantly hyperactive-impulsive Predominantly hyperactive-impulsive

typetype• Combined typeCombined type

1APA. DSM-IV. 1994.

Meeting the Diagnostic Criteria Meeting the Diagnostic Criteria for ADHD for ADHD

Presence of 6 or more symptoms of Presence of 6 or more symptoms of inattention or hyperactivity/impulsivity that inattention or hyperactivity/impulsivity that have persisted for at least 6 months to a have persisted for at least 6 months to a degree that is degree that is maladaptive and inconsistent maladaptive and inconsistent with developmental levelwith developmental level• Symptoms present before age 7 years Symptoms present before age 7 years

• Impairment from symptoms present in 2 or Impairment from symptoms present in 2 or more settingsmore settings

• Significant social, academic, or occupational Significant social, academic, or occupational impairmentimpairment

• Exclude other mental disordersExclude other mental disorders

APA. DSM-IV. 1994.

DSM IV-R criteria for diagnosisDSM IV-R criteria for diagnosis6 symptoms of6 symptoms of inattention inattention for>6months for>6months

Fails to give close attention to Fails to give close attention to details/makes careless mistakes in details/makes careless mistakes in schoolwork/activities.schoolwork/activities.

Does not listen when spoken to directly.Does not listen when spoken to directly. Does not follow through on instructions Does not follow through on instructions

and fails to finish schoolwork,chores other and fails to finish schoolwork,chores other duties.duties.

Difficulties organizing tasks and activities.Difficulties organizing tasks and activities. Avoids and dislikes to engage in tasks Avoids and dislikes to engage in tasks

that require sustained mental effortthat require sustained mental effort

ADDADD Difficulties sustaining attention in Difficulties sustaining attention in

tasks or play activities.tasks or play activities. Often loses things necessary for Often loses things necessary for

tasks or activities- toys,books, tasks or activities- toys,books, pencils, assignments.pencils, assignments.

Easily distracted by extraneous Easily distracted by extraneous stimuli.stimuli.

Often forgetful in daily activities.Often forgetful in daily activities. Daydreams in situations of stressDaydreams in situations of stress

ADHDADHDImpulsiveImpulsive Often blurts out answers before Often blurts out answers before

questions have been completedquestions have been completed Often has difficulty waiting turnOften has difficulty waiting turn Often interrupts or intrudes on Often interrupts or intrudes on

others- in conversations and others- in conversations and games.games.

Changes goals and other interests Changes goals and other interests suddenlysuddenly

ADHDADHD Symptoms that caused impairment Symptoms that caused impairment

were present were present before age of 7yearsbefore age of 7years Symptoms present in Symptoms present in two or more two or more

settingssettings Clear clinical evidence of Clear clinical evidence of significant significant

impairmentimpairment in social academic or in social academic or occupational functioningoccupational functioning

Symptoms do not occur exclusively Symptoms do not occur exclusively in PDD, SPT etc. i.e. Primary or in PDD, SPT etc. i.e. Primary or SecondarySecondary

DepressionDepression Bipolar Affective DisorderBipolar Affective Disorder Conduct disorder Conduct disorder Oppositional Defiant disorderOppositional Defiant disorder Generalized Anxiety DisorderGeneralized Anxiety Disorder OCDOCD Substance use & abuseSubstance use & abuse Hallucinations-/childhood schizophreniaHallucinations-/childhood schizophrenia MRMR

Psychiatric comorbidity

Neurological SubstrateNeurological Substrate

•The earliest indication of abnormal brain activity with ADHD came from electrophysiological studies, which demonstrated that children with ADHD exhibited lower amplitudes in brain areas believed to be correlated with attention and memory.

•In recent years, various imaging modalities have contributed both to confirming the validity of ADHD in adults and to better understanding the disorder. Magnetic resonance imaging (MRI) studies provide data showing that the prefrontal lobe and right caudate nucleus is smaller in patients with ADHD.

•In adults with ADHD since childhood, positron emission tomography (PET) scans have revealed decreased frontal cortical activity as well as abnormal regional and global glucose metabolism during the performance of a task involving executive function.

•Additionally, PET scans actually have been able to demonstrate decreased dopamine neurotransmission in the left and medial portions of the prefrontal cortex. These findings are significant because the stimulant pharmacologic agents used to ameliorate ADHD symptoms are known to increase extracellular catecholamines.• Functional magnetic resonance imaging (fMRI), a technique that maps neuronal activity within the brain by using the naturally occurring changes in blood oxygen levels that follow any neural activity, is just beginning to be applied to ADHD research. Preliminary investigations using fMRIs have been a pioneering modality in determining the etiology and pathophysiology of ADHD.• FMRI comparison of adults with ADHD vs normal controls during a Stroop interference task demonstrated failure of the anterior cingulate gyrus to activate in the ADHD subjects, suggesting that these individuals were depending on a different part of the brain to accomplish this task.

Dopamine Pathways in ADD

Dopamine Pathways in ADD

EEG and ADD

Cortical abnormalities in children Cortical abnormalities in children

with ADHDwith ADHD Results of structural brain imaging studies of Results of structural brain imaging studies of

patients with attention-deficit hyperactivity disorder patients with attention-deficit hyperactivity disorder have shown subtle reductions in total brain volume have shown subtle reductions in total brain volume and in volumes of the right frontal lobe and caudate and in volumes of the right frontal lobe and caudate nucleus. nucleus.

Although various conventional volumetric and Although various conventional volumetric and voxel-based methods of image analysis have been voxel-based methods of image analysis have been used in these studies, regional brain size and grey-used in these studies, regional brain size and grey-matter abnormalities have not yet been mapped matter abnormalities have not yet been mapped over the entire cortical surface in patients with this over the entire cortical surface in patients with this disorder. disorder.

The task of mapping these features in patients with The task of mapping these features in patients with attention-deficit hyperactivity disorder continues to attention-deficit hyperactivity disorder continues to improve.improve.

Abnormal morphology was noted in the Abnormal morphology was noted in the frontal cortices of patients with attention-frontal cortices of patients with attention-deficit hyperactivity disorder, with reduced deficit hyperactivity disorder, with reduced regional brain size localised mainly to regional brain size localised mainly to inferior portions of dorsal prefrontal cortices inferior portions of dorsal prefrontal cortices bilaterally. bilaterally.

Brain size was also reduced in anterior Brain size was also reduced in anterior temporal cortices bilaterally. temporal cortices bilaterally.

Prominent increases in grey matter were Prominent increases in grey matter were recorded in large portions of the posterior recorded in large portions of the posterior temporal and inferior parietal cortices temporal and inferior parietal cortices bilaterally. bilaterally.

The frontal, temporal, and parietal regions The frontal, temporal, and parietal regions are heteromodal association cortices that are heteromodal association cortices that constitute a distributed neural system, constitute a distributed neural system, which subserves attention and behavioural which subserves attention and behavioural inhibition. inhibition.

Physicians have identified region-specific Physicians have identified region-specific anatomical abnormalities in cortical anatomical abnormalities in cortical components of attentional systems, which components of attentional systems, which may help better account for the symptoms may help better account for the symptoms of attention-deficit hyperactivity disorder. of attention-deficit hyperactivity disorder.

Volume 362, Number 9397 Lancet / Sowell     Volume 362, Number 9397 Lancet / Sowell     

•Our morphometric procedures allow more precise localization of group differences than do the methods used in previous studies," lead author Elizabeth R. Sowell, PhD, from the University of California at Los Angeles, says in a news release.• "Our results therefore suggest that the disturbances in prefrontal cortices are localized to more inferior aspects of prefrontal regions than was previously appreciated. •Our findings also indicate that prefrontal abnormalities are represented bilaterally, by contrast to the predominantly right-sided findings that were emphasized in other reports."

•The findings are not only in brain regions controlling attention, but also in regions that subserve impulse control," says coauthor

Bradley Peterson, MD, from Columbia University and the New York State Psychiatric

Institute in New York City.

• "Disordered impulse control is often the most clinically debilitating symptom in children with

ADHD."•Although measures of the severity of ADHD symptom subtypes generally did not correlate

significantly with these morphological measures, gray matter in the occipital lobe was inversely

correlated with measures of inattention.

FMRI and ADD 8 yrs vs 28 yrs

•Pharmacotherapy is the first line of treatment for ADHD. Studies of the treatment of ADHD in childhood show that pharmacological treatment is superior to behavioral treatment and that combining the 2 treatments does not significantly improve ADHD symptoms[, although it may provide added benefit in the event of a comorbid anxiety disorder or oppositional disorder.

• Until the launch of atomoxetine, stimulant medications were the only medications to receive FDA approval for treatment of ADHD. Atomoxetine is the only medication with FDA approval for management of ADHD in adults.

•Antidepressants (for all ages) and antihypertensives (in children) are used to treat ADHD that is refractory to treatment with stimulants.

•For children and adolescents, a review of therapeutic trials shows a clear pattern of symptom improvement with stimulants, with approximately 70% of patients responding to treatment.

• Once dosage was adequately titrated for adults, studies showed similar patterns of symptom improvement. ADHD is presumed to stem from dysfunction of the catecholamine system, particularly dopamine and norepinephrine.

• Stimulants enhance transmission of catecholamines, often by blocking dopamine and norepinephrine reuptake transporters, with the net effect of increasing attention and decreasing impulsivity.

Pharmacotherapy Overview

Understanding Dopamine Understanding Dopamine Neurotransmission in ADHDNeurotransmission in ADHD

Pliszka SR et al. J Am Acad Child Adolesc Psychiatry. 1996;35:264–272.Barkley RA. Sci Am. 1998;279:66–71.Dougherty DD et al. Lancet. 1999;354:2132–2133.

Adapted from: Barkley RA. Sci Am. 1998;279:66-71.

DA receptors

DA transporters

Vesicles containing DASynaptic terminal

Postsynaptic cell

3. Dopamine in the synapse is reabsorbed (reuptake)

1. Dopamine is released into the synapse

2. Dopamine temporarily attaches to receptors

Dopamine Pathways in ADD

Studies including randomized trials have established the efficiency of stimulant medication for alleviating symptoms.

Clear indication that medication is more effective than psychosocial therapies. Effect central norepinephrine/dopamine overcoming deficits in inhibitory control and working memory.

Pharmacotherapy

Effects rapid & appear within 30 minutesShort half- life fast absorption,metabolism and eliminationPeak 1-3 hours- eliminated by 5 hoursSustain release can last up to 9 hoursShort term effects well studied need more long term studiesOne most extensive Klein MD /Mannuzza Studied effects on 226 kids over 16 yrs-no long term adverse outcomes( incl..Growth)

Pharmacotherapy

Stimulant Medication /Dosage Form(s) Available Methylphenidate

Ritalin 5mg,10mg, and 20mg tablets / Ritalin SRFocalin (d- isomer Methylphenidate) 2.5mg,5mg,10mg

Methylphenidate extended release Ritalin LA 20mg,30mg,40mg capsules

Metadate CD 10mg and 20-mg capsules /Metadate ER Concerta 18mg, 27mg, 36mg, and 54-mg caplets

Methylin / Methylin ERDextroamphetamine sulfate /amphetamine sulfate mix

Adderall 5mg,7.5mg,10mg 12.5mg,15mg, 20mg, 30-mg double-scored tabsAdderall XR 5mg,10mg,15mg,20mg,30mgcapsules

Dextroamphetamine Dexedrine 5mg, 10mg, and 15mg sustained release caps

Dexedrine( regular) 5mg and 10 mg tablets and Dexedrine 5 mg/ml elixirDextrostat spansules 5mg 10mg

Methamphetamine Desoxyn 5mg tabs

Pemoline ( Cylert) 18.75mg-, 37.5mg-, 75-mg tablets/ 37.5-mg chewable

•November 2002, atomoxetine (Strattera) was the first medication approved by the Food and Drug Administration (FDA) for the treatment of ADHD, not just for children and adolescents, but specifically for adults as well

• This is the first medication to receive an FDA indication for treatment of ADHD in adults, and in fact the initial clinical trials were done in adults rather than children.

• Atomoxetine is a highly selective norepinephrine reuptake inhibitor that lacks cardiovascular toxicity.

•Atomoxetine does not have abuse potential, minimizing the likelihood that it would be sold as a street drug. Therefore, unlike the stimulants,It is not classified as a controlled substance and does not require a special prescription.

•Atomoxetine has been shown to alleviate both inattentive and hyperactive symptoms in ADHD, with good tolerability and few adverse events.

•The dose ranges from 1.2 to 1.8 mg/kg/day in children and between 60 and 120 mg/day for adults greater than 70K. The drug is rapidly absorbed, with a half-life of 5 hours.

•Atomoxetine is a highly selective norepinephrine reuptake inhibitor that has a mechanism of action different than the stimulant drugs, making it unique among medications approved for the treatment of ADHD.

•Some understanding of the mechanism of action is valuable, as it will clarify issues relating to efficacy, tolerability, and side effects.

•Atomoxetine is a potent inhibitor of presynaptic norepinephrine reuptake. Bymaster and colleagues performed an experiment using rat prefrontal cortex brain tissue to identify atomoxetine receptor affinity and, simultaneously, demonstrate the brain area of greatest activity.• Atomoxetine was shown to have an affinity to norepinephrine but minimal affinity for serotonin (5-HT) or dopamine transporters and neuronal receptors. Extracellular concentrations of norepinephrine and dopamine were increased 3-fold by atomoxetine •In the prefrontal cortex (ie, the key region for executive function, including attention and memory), in a dose-dependent manner, but did not alter 5-HT levels or significantly affect dopamine outside of the prefrontal cortex. •Furthermore, atomoxetine was tested on over 60 other neuronal receptors, transporters, and binding sites, without finding any significant affinity.

•In contrast to atomoxetine, the researchers found that methylphenidate had a higher affinity for dopamine transporters than for norepinephrine transporters.• Like atomoxetine, methylphenidate increased extracellular norepinephrine and dopamine equally in prefrontal cortex, but it also increased dopamine in the striatum and nucleus accumbens to the same level as in the prefrontal cortex.• Interestingly, atomoxetine exhibited only small increases in dopamine in the striatum and nucleus accumbens, which are the areas of greatest concentration of dopamine transporters. Stimulants are known to work via dopaminergic neuronal pathways leading from the brain stem to the nucleus accumbens, producing positive reinforcement.• The fact that atomoxetine does not increase dopamine in this region may relate to the demonstrated a lack of abuse potential

•The most common drug-related event reported across trials has been gastrointestinal effects, such as nausea. A decrease in appetite is experienced by 15% to 20% of patients, with an initial period of weight loss that seems to appear early in treatment and then declines.

•Atomoxetine has also been associated with slight increases in diastolic blood pressure and heart rate, but no effects were seen on cardiac conduction or the QTc interval. The mild cardiac effects are comparable to the effects reported with stimulants and ADHD medications should be used with caution with patients at risk of hypertension.

STRATTERA should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing STRATTERA. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity.

Albuterol --STRATTERA should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta 2 agonists) because the action of albuterol on the cardiovascular system can be potentiated.

CYP2D6 inhibitors --Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, selective inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine

•The various stimulant formulations seem to be quite similar in their efficacy. However, the short half-life of the original formulations required multiple daily dosing.

•In recent years, long-acting formulas have been put on the market, ameliorating the stigma, inconvenience, noncompliance, and rebound associated with a short duration of action.

• The newer extended-release agents are effective for as long as 10 to 12 hours, yet some patients are still requiring additional short-acting stimulants to extend their treatment time.

• The current doses that are available are often too low for adults, requiring them to take several pills and sometimes this means paying considerably more for the medication or having the needed dose refused by the insurer.

AmphetamineAmphetamine MethylphenidateMethylphenidate

AbsorptionAbsorption Acidic foods limit absorptionAcidic foods limit absorption Readily absorbed; Readily absorbed; independent of pHindependent of pH

DistributionDistribution Low plasma protein bindingLow plasma protein binding Low plasma protein bindingLow plasma protein binding

MetabolismMetabolism pH of urine determines pH of urine determines degree of hepatic clearancedegree of hepatic clearance

Moderate PModerate P450450 metabolism, metabolism, some CYP2D6some CYP2D6

Presystemic metabolism Presystemic metabolism limits oral bioavailabilitylimits oral bioavailability

Little Little PP450450 metabolism; no metabolism; no CYP2D6 metabolismCYP2D6 metabolism

EliminationElimination Acidic urine results in Acidic urine results in decreased plasma half-life decreased plasma half-life and increased renal and increased renal clearanceclearance

Shows up on routine drug Shows up on routine drug testingtesting

Elimination of MPH Elimination of MPH metabolites unaffected by metabolites unaffected by urinary pHurinary pH

Does Does not show up on routine drug not show up on routine drug testingtesting

Methylphenidate vs AmphetamineMethylphenidate vs Amphetamine

Newer StimulantsNewer Stimulants

Vyvanse (lysamphetamine)Vyvanse (lysamphetamine)

-dosages 10 ,20,30,40,60,70 mg-dosages 10 ,20,30,40,60,70 mg

ZENZEDIZENZEDI

-dosages 5mg, 7.5mg, 10mg.-dosages 5mg, 7.5mg, 10mg.

Quillivant liquid MPDQuillivant liquid MPD 10ml = 4 mg10ml = 4 mg

Selection of the Optimal Dose Selection of the Optimal Dose Ratio for MetadateRatio for Metadate®® CD CD

1Wigal et al. J Appl Res 2003;3:46-63

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30:70 prototype (25 mg) 40:60 prototype (25 mg)

Biphasic Release Pattern of Biphasic Release Pattern of MetadateMetadate®® CD Capsules CD Capsules

1Metadate® CD (methylphenidate HCl, USP) Extended-Release Capsules, full Prescribing Information. Celltech Pharmaceuticals, Inc, Rochester, NY; R312D (07/03)

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•Generally, stimulant medications are well tolerated. Side effects from stimulants include insomnia, headaches, weight loss or anorexia, tics, anxiety, and dysphoria.

•Cardiovascular effects typically involve only mild increases in heart rate and blood pressure, but need to be more closely watched in adults than in children

•.Adults who present with borderline hypertension may not be able to tolerate even a mild increase. In this circumstance the hypertension should be treated before stimulant is reinstituted.

• Insomnia is common for adults with ADHD both before and after initiation of a course of a stimulant. A delay in sleep onset may decrease with longer administration of the medication.

• Stimulant medication is initially administered by titrating the dose until symptoms are well controlled and, concurrently, side effects are manageable for the patient.

•Both methylphenidate and dextroamphetamine are C-II controlled substances and much has been written in medical and popular literature about their potential for abuse, necessitating clarity on the issue.

•An adult who suffers from ADHD, uses the medication as prescribed, and does not concurrently have a substance abuse problem will not become addicted.

•There are reports of stimulant medication prescribed medically being diverted for nonmedical recreational use. Clinicians should therefore be circumspect in prescribing medication to patients with current substance abuse, or whom they suspect might sell the drug.

•Interestingly, some studies offer intriguing evidence that stimulant treatment of ADHD does decrease the risk of future substance abuse, including cocaine use, among adult ADHD sufferers.

Key points:

•Pharmacotherapy is a central element in the treatment of ADHD, and some studies have shown it to be more effective than behavioral treatment in reducing the symptoms of ADHD.

Stimulants increase dopamine and norepinephrine levels in the synapse, ameliorating symptoms associated with ADHD in about

70% of patients.

Side effects from stimulants can include hypertension, insomnia, headaches, weight loss or anorexia, tics, anxiety, and dysphoria.

When prescribed and taken appropriately for the treatment of ADHD, stimulant medication is not addictive. Care should be taken when using stimulants to treat patients with a comorbid

substance abuse disorder.

Desoxyn (Methamphetamine Hcl)Desoxyn (Methamphetamine Hcl) Adipex-P (Phenteraimine)Adipex-P (Phenteraimine) Didex (Benzphetamine)Didex (Benzphetamine) Tenuate (Diethylpropion Hcl)Tenuate (Diethylpropion Hcl) Mazindol (Imidazoisoindol)Mazindol (Imidazoisoindol) Phenazine (Phendimetrazine Phenazine (Phendimetrazine

Tartarate)Tartarate) Dopram (Doxapram Hcl)Dopram (Doxapram Hcl)

Other Stimulant Medications

ClonidineClonidine Adverse effects, sedating, Adverse effects, sedating,

hypotensionhypotension

GuaifenesinGuaifenesin Adverse effects - few & less Adverse effects - few & less

sedatingsedating

*Both are often used in combination *Both are often used in combination with other medications to augment with other medications to augment treatment.treatment.

Alpha 2 adrenergic agonists

ProzacPaxilZoloftTofranilEffexor SRLexapro

Generally Maximum benefit in co- morbidity

AntidepressantsDesipramine (Norpramin), a tricyclic antidepressant that blocks norepinephrine and serotonin uptake, and bupropion (Wellbutrin), an antidepressant with greater dopamine reuptake block than most antidepressants, have been shown to have some effectiveness in treatment of ADHD.

Melatonin Melatonin Melatonin may be helpful for treating Melatonin may be helpful for treating

delayed sleep onset in children with delayed sleep onset in children with attention deficit-hyperactivity disorder attention deficit-hyperactivity disorder (ADHD), (ADHD),

Since melatonin is in an unusual category, Since melatonin is in an unusual category, being an unpatentable hormone being an unpatentable hormone considered in the U.S. to be a 'nutritional considered in the U.S. to be a 'nutritional supplement' that is unregulated by the supplement' that is unregulated by the [Food and Drug Administration], and since [Food and Drug Administration], and since there is evidence that some brands there is evidence that some brands contain other than 'pharmaceutically pure' contain other than 'pharmaceutically pure' melatonin, evidence of safety and efficacy melatonin, evidence of safety and efficacy is of great importance to clinicians is of great importance to clinicians

•Transcranial magnetic stimulation (TMS) is a newly developed tool for assessing functionality of the central nervous system (CNS). After Baker et al. demonstrated its value in humans in 1985, single and paired-pulse •TMS have proven useful in detecting clinical and subclinical abnormalities in a large array of neurological and neuropsychiatric disorders including Tourette's syndrome, obsessive compulsive disorder, depression, schizophrenia, bipolar disorders and ADHD among others.•Regarding ADHD specifically, TMS seems to be an ideal method for studying the maturational process of the motor pathways since it clearly excites the corticomotoneuronal system presumed to be involved in this disorder.

Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool, New Therapy and New Hope for ADHD

•Using single stimulation in children with ADHD, found a prolongation of central motor conduction time as well as some side-to-side stimulation differences compared with those found in age- and sex-matched controls. These findings demonstrated a delay in the maturation of the corticomotoneuronal system in patients with ADHD.• Moll et al.[11] reported that children with ADHD had significantly reduced intracortical inhibition (ICI) with a normal intracortical facilitation compared to healthy controls and such ICI showed improvement after giving 10 mg of MPH.

•However, most of the morphophysioneurochemical hallmarks of ADHD involving prefrontal-caudate-cerebellar pathways with noteworthy dopaminergic abnormalities have not yet been taken into account. Therefore we consider that they should be the current focus if rTMS is to be employed as a therapeutic option.

•rTMS has been found effective in Parkinson disease, depression, obsessive-compulsive disorder, Tourette's syndrome and some types of tic.• With regard to children rTMS has been tried with a small number of patients with action myoclonus, progressive myoclonic epilepsy, bipolar disorder, major depression and schizophrenia with some promising, albeit, short-lasting positive results.• Some of these disorders are due to dopamine abnormalities and share some genetic, clinical, biochemical, neuranatomical and neuro-behavioural similarities with ADHD.• Even though a complete understanding of the mechanism of action of rTMS has not been developed, it is now clear that rTMS at low frequencies could cause long-term depression of cortico-cortical transmission in normals as well as improvement of symptoms of some neuropsychiatric disorders commented on above, including the modulation of several neurotransmitters such as dopamine and its metabolites (e.g. homovanilic acid) mainly after prefrontal cortex stimulation.

•Some safety issues must be considered in some of patients since there is a limited experience of possible side-effects in children and adolescents using TMS particularly rTMS.[] Even though muscle-tension headache that resolved promptly is the only only side-effect found in children receiving rTMS,

•Tis still concern in applying it with pulse frequencies of 50 Hz or more for periods of several seconds because of the possiblity of seizures.

• At present, there is no reason for applying rTMS at higher frequencies, intensities or with longer train durations than those employed in clinical or research studies.

• Thus, frequencies lower than 50 Hz might be used with some confidence in humans until new safety guidelines on rTMS applications can be published

ADHDADHDParent Parent Information & educationInformation & education Child management skillsChild management skills

SchoolSchool Evaluation / PPT (Pupil Placement Evaluation / PPT (Pupil Placement

Team)Team) Teacher training / Special educationTeacher training / Special education School NurseSchool Nurse

DoctorDoctor DiagnosisDiagnosis Information & treatmentInformation & treatment

ADHDADHDRole of SchoolRole of School Evaluation-medical & psychologicalEvaluation-medical & psychological PPT (Pupil Placement Team)PPT (Pupil Placement Team) Learning Disability definition & Learning Disability definition &

placementplacement Teacher Training in ADHDTeacher Training in ADHD Teacher documentation( changes Teacher documentation( changes

with treatment, feedback to with treatment, feedback to Parents etc)Parents etc)

School Nurse -medication School Nurse -medication documentation & dispensationdocumentation & dispensation

ADHDADHD

Contingency management : point Contingency management : point token, reward systems- time outtoken, reward systems- time out

Cognitive Behavioral trainingCognitive Behavioral training

(self monitoring,verbal self (self monitoring,verbal self instruction solving strategies, self instruction solving strategies, self reinforcement)reinforcement)

Parent training /child management Parent training /child management skillsskills

•Hallmark characteristics of attention-deficit hyperactivity disorder (ADHD) include hyperactivity, impulsiveness, and inattentiveness. •Research has established that ADHD, still the most common psychiatric disorder in children, can persist not only through adolescence but into adulthood as well.• While ADHD can remit, an estimated 30% to 70% of childhood ADHD cases continue into adulthood. However, much of what we know about ADHD comes from the wealth of research that has been collected on its manifestations• In childhood. Increasingly, evidence points to a developmental shift in the presentation of ADHD in adults. This shifting profile may well have resulted in underdiagnosis of adult cases of ADHD.

ADHD is a developmental disorder, which by definition must have been present from childhood. Many of these adults may not have had the opportunity to be assessed or diagnosed, since ADHD services and expertise may not have been available.

More recently investigators have shifted their focus of interest towards understanding the nature of attention problems and the executive functions. Executive function refers to skills such as working memory, planning, prioritization, organization, and time management. The theory holds that the prefrontal lobes, which are associated with memory, motivation, and synthesis of behavior, are the site of the brain's executive function and regulate behavior via a process of inhibition. Advances in neuro imaging technology and the development of neuropsychological assessments have permitted researchers to measure and quantify executive function in adults with ADHD as compared with controls.

Many of the associated symptoms of ADHD involve dysregulation of sleep, appetite, energy, and mood that are easily understood within the framework of mood disorders with which adult psychiatrists are more familiar. Most patients with ADHD also have another comorbid disorder. The adult psychiatrist may attribute the patient's impairment to the comorbid disorder more familiar to him (ie, anxiety disorder, bipolar II disorder, or personality disorder) and miss the contribution of the ADHD. Some of the comorbid disorders that accompany ADHD are developmental disorders in their own right that adult psychiatrists do not recognize such as Asperger's syndrome, learning disabilities, Tourette's syndrome, or oppositional defiant disorder

The research that identified the continued prevalence of ADHD in adults had also identified a pattern of lifelong adaptive functioning difficulties. The maladaptive patterns might manifest with or without comorbidities -- each topic will be covered in sections to follow. What began as a problem functioning in the classroom and playground became persistent social and vocational troubles, if not failures. Research has demonstrated that adult ADHD is associated with functional impairments that result in an array of problematic behaviors, such as increased traffic accidents and violations, difficulty with smoking, educational and occupational impairment and marital problems.[] In addition, ADHD was shown to predict specific disorders in adulthood, such as antisocial behavior and substance abuse.[11] Given the studies showing that patients who receive pharmacological treatment have an 85% reduction in risk for substance abuse, it is unfortunate that establishing validity of ADHD in adults was so lengthy a process.

Key points:

It is well established that ADHD affects some individuals across their lifespan.

Prospective studies illustrate that adults diagnosed with ADHD as children retained at least one ADHD

symptom into adulthood.

Sequelae of ADHD may continue to impair the lives of individuals with ADHD throughout adulthood,

particularly those who have not received treatment.

Key points:Hyperactivity tends to decrease with age, while problems with sustained attention persist and

predominate the symptom profile in many adults.

Adults exhibit impairments in the brain's executive function both at home and at the workplace.

While all 3 core symptoms can persist over a lifetime, adults with ADHD may have more attenuated

symptoms that are expressed in manners different from children

•It is estimated that nearly 75% of adults with ADHD have a comorbid condition, with reports ascertaining that 77% of this population has had at least 1 of 17 comorbid psychiatric disorders.

• Comorbidity immeasurably complicates the diagnosis of ADHD and, as will be discussed in the section on diagnosis, is not excluded for an accurate diagnosis of ADHD, according to DSM-IV criteria. The inclusive standard is likely based on an accumulation of research,

•Indicating that the comorbidities are indeed discrete conditions in their own right. As one group of researchers states, "among adults, ADHD does not appear to be an artifact of symptoms shared with other psychiatric disorders (eg, major depression, bipolar disorder, generalized anxiety disorder) nor are the comorbidities themselves the result of symptomatic overlap with ADHD.

Key points:Approximately 75% of adults with ADHD have at least 1 comorbid

condition.

Learning disabilities and disruptive behavior disorders are the 2 comorbid conditions most prevalent in childhood.

Adults with ADHD are at considerable risk for substance abuse (especially marijuana), and smoking, but this risk is diminished by

appropriate treatment.

Mood and anxiety disorders are significant comorbidities among adults with ADHD but more research is needed to determine their

prevalence.

While researchers may disagree about age of childhood onset in diagnosing adult ADHD, all agree that ADHD is not an adult-onset disorder and must be verified from

childhood. An assessment of ADHD symptoms and behavior from childhood may include any or all of the following:

The Wender Utah Rating Scale (WURS) is designed to measure whether the adult had ADHD in childhood.

School report cards, if available, might include comments about behavior problems, poor focus, lack of effort, or underachievement relative to the student's potential.

Parents may serve as collateral informants and complete an ADHD scale with respect to the individual's symptoms in childhood.

The adult may self report symptoms in childhood on a diagnostic interview or on an ADHD scale completed for childhood symptoms.]

The developmental history would be consistent with ADHD, including evidence of problems with peers, other delays such as enuresis, school failure, suspensions, or

special interventions such as sitting in front of the class, etc.

Symptom rating scales.

Conners Adult ADHD Rating Scale -- available either in 26- or 42-item version, perhaps the best scale available to discriminate between patients with ADHD and those with other conditions; internal reliability and validity ratings are high (available from Multi-

Health Systems at mhs.com).

DSM-IV-based rating scales list the 18 items of DSM-IV ADHD (and sometimes those for oppositional defiant disorder and conduct disorder as well) along with a 4 point scale.

The patient rates each item as:

0. Not at all or never1. Somewhat or sometimes

2. Pretty much or often3. Very much or very often

Scores of 2 or 3 are usually considered to be in the clinical range. If 6/9 items of inattention and/or hyperactive/impulsive symptoms are rated 2 or 3 this would be

considered to have met the DSM-IV categorical cutoff. Several versions of this scale are available, and 1 is available on the net. Barkley has adapted this scale for use with

adults.

•Neuropsychological assessments were initially developed for children and established that children evidenced clinically significant deficits in executive functioning, even when IQ scores were above average.•Neuropsychological assessments performed on adults with ADHD reveals deficits in speed, memory, and attention. However, research on these measurements demonstrates that the spectrum of deficit functions associated with ADHD is not consistent across the various neuropsychological tests available for adults. •Therefore, neuropsychological testing of adults may contribute to an overall evaluation but, again, should not be used as the sole diagnostic instrument. The same is true for computerized tests of attention such as the Continuous Performance Test (CPT) or Test of Visual Attention (TOVA).

•Compared with children who have problems in both cognitive and behavioral control, adults with ADHD have greater deficits in the use of executive functions relating to cognitive control.

•As the years pass, the 3 core dimensions of the disorder do persist in some form.[] However, the demands on the brain's executive function to regulate, organize, and manage behaviors both at home and at the workplace become ever more complex.

•Experts suggest that failure of the brain's executive functions is 1 of the most prominent attributes in adult ADHD.

Hyperactivity -- not excessive action itself, but the inability to control arousal and amount of activation

Inattentiveness -- not a global inability to focus per se, but rather the inability to sustain, shift, and establish attention to particular tasks the

individual finds boring but are nonetheless essential to adult functioning

Impulsiveness -- no longer the inability to control actions, but the inability to determine when and how actions should be expressed and

sequenced, and continued environmental dependency where circumstances control action, rather than the other way around

Cognitive TherapyCognitive Therapy

‘Thought”Potentials

FOCUS “Now”Requirement

GOAL

“Stray”Deflection

Nebula

                                                                                                                                                                            

      

                                                                                                                              

                                                                                                                                                                                                                                                                        

        

Plague