Attention Deficit Hyperactivity DisorderADHD

The diagnosis of ADHD is complex

(DSM IV vs DSM V criteria) will be covered with Prof. Megan.

ADHD World Wide

7% of children around the world have ADHD ADHD diagnosis has increased Number of children receiving ADHD medication has increased

What is ADHD?

A common childhood disorder. It can continue to adolescence and adulthood.

How do they work in general terms? ADHD drugs

All of the pharmacological agents used in ADHD increase the levels of catecholamine neurotransmitters in the prefrontal cortex

Atomoxetine Drug facts

Approved for adults as well, only drug with FDA warning of increased suicidality (0.4% vs. 0% in placebo).

Can ADHD be Cured?

As many conditions and disorders, current drugs do not cure ADHD but control the symptoms. Medication can help a child complete school-work by paying more attention. Adding behavioral therapy, counseling, and practical support can help children with ADHD and their families to better cope with everyday problems. Medications work best with follow ups with the child's doctor.

Non-Stimulants

Atomoxetine-Strattea Buproprion-Wellbutrin Clondidine HCL- Kapvay Guanfacine- Infuniv

Methylphenidate (MPH) MOA

Blocks more than 50% of DAT, some MAO inhibition but not like AMPH

Atomoxetine MOA

Blocks the NE transporter increases NE and DA in prefrontal cortex

Guanfacine and Clonidine Drug facts

Both are approved as monotherapy or adjuncts to stimulants in ADHD- but not as effective as stimulants when used as monotherapy (not studied in adults)

Amphetamine Drug facts

Central Stimulant, different MoA than cocaine but similar effects

This kid is distracted, which means

DA and NE are not working as well as they should!!

Stimulants

Dextroamphetamine-Dexedrine Amphetamine + dextroamphetamine -Adderall Lisdexamfetamine-Vyvanse ® Methylphenidate-Ritalin ®

ADHD Symptoms

Difficulty staying focused and paying attention. Difficulty controlling behavior. Hyperactivity (over-activity).

Dextroamphetamine

Drug Facts: MoA similar to MPH MoA: Blocks DAT increase DA in synaptic cleft ADR: Similar to amphentamine

Lisdexamfetamine

Inactive prodrug and converted to dextroamphetamine Conversion is not affected by GI pH Developed to provide long-term duration of effect and reduced abuse potential Blocks both reuptake of DA and NE via the DA transport (DAT1) and by blocking intraneuronal vesicular monoamine transport to release DA and NE

Key Behaviors in ADHD

Inattention Hyperactivity Impulsivity

Amphetamine ADR

Increases HR and BP due to alpha and beta receptors stimulation

Amphetamine MOA

Increases the release of NE and DA from the stores catecholamine, inhibit DA and NE reuptake and inhibit MAO that will expedite the process of increasing catecholamine neurotransmitters in the synaptic cleft.

Therapeutic effects ADHD Drugs

Increasing DA is thought to weaken the inappropriate network connection "produces a decrease in noise" Increase in NE is thought to strengthen appropriate signals "increase in signal" Despite they work (in general terms) to enhance "DA and NE" in the prefrontal cortex, the different stimulants seem to have a broad affect on ADHD Non-stimulants are likely to have more specific effects

Amphetamine Therapeutic use

Limited, tolerance and dependence

Methylphenidate (MPH) Important findings

MPH significantly enhances DA in the basal ganglia affected by age, older subjects show less effect (this is because the effect relies on DA release) MPH therapeutic effect are due to enhancing DA signaling and this is dependent on DA release which varies from one patient to another

Environment Factors ADHD Prenatal Environment:

Maternal stress during pregnancy Prenatal exposure to tobacco, alcohol and other drugs/environmental toxins pregnancy/birth complications Low birth weight/prematurity

Atomoxetine PK

Metabolism: CYP2D6 (poor vs. extensive metabolizer's) Slow onset of action (takes 2-4 weeks to see effect vs stimulants 1-2 hrs) Can take up to 12 weeks before seeing full benefit.

Amphetamine PK

Metabolized by a range of CYP 450 enzymes including 2D6 (PGx/drug-drug interactions)

Methylphenidate (MPH) Drug facts

Most commonly prescribed drug for ADHD, derivative of AMPH

Genetic Association Studies

Most consistent data has been shown for the following genes: DA receptor D4 (DRD4) DA receptor D5 (DRD5) DA transporter (SLC6A3/DAT1) Serotonin receptor 1B (HTR1B) Serotonin transporter (SLC6A4/5HTT) Synaptosomal-associated protein 25 (SNAP-25

Environment Factors ADHD Postnatal Environment:

Neonatal anoxia and seizures Brain Injury Exposure to lead and polychlorinated biphenyls Psychosocial adversity: ex. Familial issues (conflict, parenting after a different parent)

Neurobiology of ADHD

Neuroimaging studies have reported reduced white matter (WM) volumes in ADHD patients. Studies conducted on the cortical development in ADHD children showed a marked delay in brain maturation. The delay was most prominent in the prefrontal regions which are important in attention and motor planning. Two neurotransmitters: NE and dopamine, play a critical and essential role in prefrontal cortex function.

Neurobiology of ADHD

One of the most typical patterns seen in brain maps, where a child with ADHD has under active (red) frontal lobe.

Methylphenidate (MPH) PK

Oral MPH has been found to reach peak levels in the brain 60-90 minutes after administration

ADHD Genetic Factors

Relative of ADHD patients are at an increased risk Supported by twin and adoption studies Adoption studies show increased ADHD rate among biological relatives vs. adoptive families Twin studies estimate a heritably of 76% in children and adolescents Heritability estimates in adults in lower ~ 30% suggesting environmental factors play a larger role in this group

Who is at Risk? (for ADHD)

Runs in the family, heredity is the most common cause of ADHD. Mothers who smoke during pregnancy or consume alcohol. Exposure to lead. Injury to the brain or trauma.

Can you Outgrow ADHD?

Some children with ADHD were shown to eventually "catch up" with normal children without ADHD, suggesting a delay in cortical maturation Genetic markers can help clinicians determine children who are more likely to outgrow their ADHD

Guanfacine and Clonidine MOA

centrally acting α2-receptors agonists, presynaptically they inhibit NE release and postsynptically they increase blood flow in the prefrontal cortex enhanced blood flow enhances executive function and memory

Dopamine

enhances prefrontal cortex function by decreasing noise. In other words, if your mind does not demand it, dopamine will act to suppress those inputs by stimulating the appropriate postsynaptic receptors

Norepinephrine

enhances prefrontal cortex function by increasing the input of the signals you need/demand by stimulating the appropriate receptors

It is worth noting that ADHD is a label for a

heterogeneous collections of dimensional behaviors that appear to have heterogeneous causes, increasing the complexity of diagnosis

A variety of brain sub-regions impacted ADHD

including frontal and parietal cortexes, basal ganglia, cerebellum, hippocampus, and corpus callosum

Recall when we talked about high doses of AMPH effect in causing

indistinguishable psychosis from schizophrenics

The combination effect of change in brain structure and neural networks in ADHD lead to

organized brain phenotypes

Complexity of ADHD:

same intermediate phenotype can be generated by variants identified in many genes

Guanfacine and Clonidine PK/ADR

t1/2 of Guanafacine is longer than Clondine (18 vs 12 hrs) dose dependent hypotension (why?)