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?)