NUTR 4320 Lecture Notes - Attention Deficit Hyperactivity Disorder Predominantly Inattentive, Magnetic Resonance Imaging, Norepinephrine Reuptake Inhibitor
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ADHD: Primarily characterized by a “persistent pattern of inattention and/or hyperactivity- impulsivity that is
more frequent and severe than is typically observed in individuals at a comparable level of development”
Prevalence 3-7 % school age children in USA and Canada
High comorbidity (50-60%) with ODD, OCD, depression, anxiety, 25-30% have learning disabilities, 60%
diagnosed as children -symptoms persist into adulthood
1. Criterion A must be present
2. Symptoms must be present before the age of 7 years (Criterion B)
3. Some impairment from the symptoms must be present in at least two different settings
(Criterion C- home, school, work).
4. Clear evidence that symptoms are interfering with developmentally appropriate social,
academic or occupational functioning (Criterion D)
5. The disturbances must not be confined to those periods during the course of a Pervasive Developmental
Disorder, Schizophrenia or other Psychotic Disorder, and must not be better explained by another mental
disorder (Mood, Anxiety, Dissociative, Personality) – Criterion E
ADHD – Combined Type – six or more symptoms of inattention with six or more
symptoms of hyperactivity-impulsivity for at least 6 months
ADHD- Predominantly Inattentive Type – six (6) or more symptoms of inattention but
fewer than six of hyperactivity-impulsivity for at least 6 months.
ADHD- Predominantly Hyperactive-Impulsive Type – six (6) or more symptoms of
hyperactivity-impulsivity but fewer than six symptoms of inattention
The Conners’ Teacher and Parent Rating Scales (CTRS and CPRS) rate children on several aspects of behaviours
related directly to DSM-IV diagnostic criteria and allow comparison of results against a normative sample of
over 8000 North American children. A score of > 65 is diagnostic of ADHD.
Abnormalities in dopamine neurotransmission in parts of brain that control focus and
attention detected by brain monitoring techniques such as magnetic resonance imaging
(MRI), and functional MRI (fMRI) have established that ADHD
may be organically expressed in the brain.
MRI- a test that uses a magnetic field and pulses of radio wave energy to take pictures of the head.
MRI studies suggest localized abnormalities in the right prefrontal cortex, basal ganglia,
globus pallidus, corpus callosum and loss of the normal caudate symmetry.
Structural or functional abnormalities in the connections between the frontal cortex and
the basal ganglia.
Decreased blood flow in the frontal areas of children with ADHD. Reduced brain glucose metabolism in the
frontal lobes of the brain has also been shown
using PET scans in ADHD children when they have been asked to concentrate on a task.
Neurochemical studies suggest that alterations in catecholaminergic (mainly
dopaminergic and noradrenergic) transmitter functions markedly contribute to the
symptoms of ADHD.
1. Methylphenidate (Ritalin, Concerta) – enhances neurotransmission via dopamine and
norepinephrine primarily in the striatum. Increases focus and attention but can decrease sleep and appetite.
2. Atomoxetine (Strattera) non-stimulant drug – newer-selective norepinephrine reuptake
inhibitor – increases NE levels in brain. Other activities and exact mechanism(s) are not known.
3. Dextroamphetamine sulfates (Dexedrine) –inhibits reuptake of dopamine and norepinephrine
and possibly others. It increases mental alertness, decreases fatigue and increased motor activity and mild
euphoria. Side effects include increased heart rate, vasoconstriction and bronchial dilation. Used in about 10%
Response rate ~ 70% and up to 90% will respond to at least one drug if titrated carefully
4. Amphetamines (Adderall, Focalin, Attenade)
5. Tri-cyclic antidepressants (Desipramine, Imipramine) for non-responsive patients
OMEGA 3s- inhibit hepatic synthesis and possibly apoprotein synthesis of plasma lipids, mainly TAGs.- replace
arachidonic acid (AA, 20:4n-6) with eicosapentaenoic acid (EPA, 20:5n-3) or docosahexaenoic acid (DHA, 22:6n-
3) in phospholipid pools
when these fatty acids are released from phospholipids as a result of the action of
phospholipases, they can inhibit cyclooxygenases and lipoxygenases which in turn decreases the production of
TXA2 and LTB4 and eicosanoids by several cell types including platelets and macrophages.
associated with alterations in blood viscosity,decrease blood pressure, alter membrane enzyme and receptor
Neural cells contain high levels of LCPUFAs including AA and DHA. DHA in particular is
found mostly in PE and in synaptosomal membranes and photoreceptor outer segments
Codliver oil (extremely high cholesterol), madhadden oil, makeral have highest DHA + EPA levels. Lowest = cod.
STUDY Vaisman et al determined whether conjugation of EPA or DHA to PL or TAG made any
difference and whether either affected visual performance.
Gave about 250 mg of EPA+DHA per day to 60 children av age 9 yr.
Used a TOVA (Test of Variables of Attention) age and sex-normalized computer-based
assessment of inattention at baseline and 3 mo intervention.
Outcomes – slight increase in n-3 fatty acids in both supplement groups in serum PL and
erythrocyte PL, some improvement in TOVAs suggested PL better than FO but very
small changes overall. Improvements correlated best with changes in DHA.
Some studies show no effect.
STUDY: EPA supplementation improves teacher-related behavior and oppositional symptoms in children with
500 mg/d EPA or placebo, 92 children, 7-12 yr, 15 wks. Showed most improvement in either children with
primarily oppositional behaviour or those with relatively mild hyperactivity symptoms rather than total
Conner’s Score.No changes in DHA levels, huge increases in EPA and small decreases in AA so EPA/AA ratio
Hamsters: omega 3 deficiency=decreased melatonin secretion. There have been observed abnormal circ
rhythems in kids with ADHD. MEL may modulate dopamine function. dampening of the MEL rhythm induces
activation of dopaminergic and glutamatergic functions, weakens the circadian clock and thus plays a role in
sleep/wake rhythm and in hyperactive and emotional behaviors.
BDNF (brain derived neutropic factor): Roles in differentiation and survival of dopaminergic and serotonergic
neurons. Met allele =affects intracellular processing and secretion of BDNF -associated with hippocampal
function, episodic memory, schizophrenia and eating disorders. Val allele associated with substance-related
disorders, bipolar disorder and extraversion. both alleles have been associated with ADHD
Pathology. A lowered BDNF activity may result in a dysfunction of the midbrain dopaminergic system, thought
to be an important aspect of ADHD pathogenesis.
· BDNF may also be important in initiating dopamine release in response to amphetamine, important in
treatment of ADHD.
Steroid Sulfatase: highly expressed in various epithelia during development. Cleaves sulfate from various
hormones including dehydroepiandrosterone sulfate
(DHEAS), thereby controlling their activity in the brain. Systemic levels of DHEA appear to correlate with ADHD
methylphenidate treatment may exert its therapeutic effect in ADHD through increasing
· STS knockout mice have attention deficits, impulsivity and increased aggression.
MAJOR DEPRESSIVE DISORDER (MDD)
DIAGNOSIS- EEG or NTs? Mostly talk to doctor one or more major depressive episodes (lasting > 2 weeks of
depressed mood or loss of interest accompanied by ≥ 4 additional symptoms of depression).
Abnormal Sleep EEG observed 40-60% of outpatients, 90% inpatients
Dysregulation of a of neurotransmitters: Serotonin NE Dopamine Acetylcholine GABA
Disturbances in corticoltropin releasing hormone, increased cortisol, TSH GH response to prolactin.
Alterations in cerebral blood flow using functional brain imaging techniques
Culture strongly influences experience and communication of symptoms.
Theory of etiology=abnormaliy in monoamine neurotransmission affecting predominantly serotonin and NE.
Ach-choline-CNS parasmpatheic nerves; 5HT-tryptophan-CNS, endochraffin cells of gut and enteric cells. GABA-
glutamate-CNS; Epi –Tyrosine- Adrenal medulla some CNS; NE-tyrosine-CNS sympathetic nerve cells; dopamine
– tyr-CNS; NO- arginine-CNS GIT
Major problems with theory
1.antidepressant drugs produce their biochemical effects within minutes or hours, however the therapeutic
benefit usually takes weeks.(2).Level of monoamine depletion and severity of depression do not necessarily
correlate (3)Suggestion that phosphorylation of key signaling molecules is critical to the activity of
drugs and their purported benefits (4) Adaptive changes in NMDA receptors must occur for clinical benefit and
this takes weeks.
STUDY: synaptic disfunction in depression demonstrates that depression is assoc with size of brain areas
that regulate mood and cognition (frontal cortex and hippocampus- neuronal synapses in these areas).
KETAMINE: NMDA (N-acetyl D-aspartate) re antagonist. Produces rapid response in patients who are resistant
to typical Ads rapidly induces synaptogenesis and reverses synaptic deficits caused by chronic stress.
MAOi’s—high in liver and neurons half- life of NTs in synapse. Interaction w/ other drugs, food components
(tyramine) that act on MAO system=serotonin syndrome.
Side effects= altered mental status. Agitation. Diaphoresis. Hyperthermia. Hypertonicity if untreated
Tricyclic Ads: non-selective re-uptake of monoamines=life in synaptic cleft longer. SEs: drowsiness, wt gain, dry
mouth, urinary retention, constipation, blurred visioin BP.
SSRIs: reuptaketime of 5-HT in synaptic cleft. There is an in brain activity in cortex in response to –ve
stimuli this is suppressed when 5HT is . Ie ADs could work by suppressing the activity of overactive
neuronal circuits. Side effects: sexual disturbances, GI distress, drowsiness etc. risk of birth defects risk of
pulmonary hypertension, baby: risk of lung problem where circulatory system doesn’t adapt to being outside
of womb. May worsen depression symptoms + suicidal thoughts/ behavior. SRNIs=very similar.
Tetracyclic Ads: prevent neurotransmitters from binding with nerve cell receptors called alpha-2
receptors=more NE and 5-HT in synapse. SEs: drowsiness, wt gain, dizziness, thirst, muscle/joint aches,
constitpation, apetite, cholesterol, agranulocytosis ie; risk of infection.
NUTRIENT-DRUG INTERACTIONS: AA availability!Trp or Tyr:LNAA compete at BBB
Trp:LNAA- response for TCAs, SSRIs and combo therapy, no effect on MAOis.
Another study: Trp/LNAA or Tyr/LNAA correlated w/ SSRI or TCA.
**whether one can regulate re levels may be important- not just AA level but activity of NT re levels**
One study showed that co-administration of trp with SSRIs lead to a significant improvement in depressive
symptoms in the first week of pharmacotherapy but not at later time points
α-lactalbumin – whey – trp rich - decreased depressive symptoms in stress-susceptible subjects
FOLATE B12 and HOMOCYSTEINE
Low folate =BH4 (Tetrahydrobiopterin)- BH4 is required for Trp and tyr hydroxylase= production of
catecholamines of serotonin.
Low folate is assoc w/ low treatment response to SSRIs, lifetime diagnosis of MDD. Meta analysis=depressed
patients had levels of homocysteines, B12, and folate.
-15mg/day folate in MDD patients or schizo = improvement
S-adenosylmethionine: Cofactor for rate-limiting enzymes trp hydroxylase and tyr hydroxylase. s level of
synapsin 1- regulates the # of vesicles available for exocytosis shown in hippocampal and frontal cortex nerve
terminals in rats.
depression scores at 400mg/day at 7 and 15 days.
Zinc: some studies: levels lower in depressed patients. -regardless of baseline levels, Zn levels rise after
successful treat. Rat model: zn hippocampus response to SSRI and ECT. Mechanism?? Alter NMDA or nAch Re?
B6: low B6 assoc w/ long term use of MAOi’s. B6 deficiency is alleviated via pyridoxine supplements.
Mechanism: non-enzymatic conjugation of B6 w/ the drug which is then excreted primarily in the urine.
Tyramine=monoamine in food. MAO deaminates tyramine. Risk of hypertensive crisis dramatically Has
vasopressive activity on its own, plus promotes NE release from nerve terminals → ↑ BP. Sudden severe
headache, pallor, chills, neck stiffness OR palpitations, hypertension, chest pain, apprehension, headache, pallor
and collapse Intracerebral hemorrhage and death. Foods: broad bean pods, fermented meat, spoiled meat,
aged cheese, tap beers (no pasteuirization)
Omega 3: high levels of omega 3 associated with lower incidence of depression ( ie Japan and Taiwan= low
incidence, New zealand and canada are high).
Subjects w/ major depression= omega 6 omega 3 status.
Perilla seed oil and flax seed=very high SCFAs but no LCPUFAS herring and salmon oil is best for
omega3:omega6 ratio. LCPUFAs = fish only!
1g/d effectively treated depressed subjects on Ads Mechanism: -Mood disorders may be caused by impaired PL
metabolism or fatty acid related signal - N-3s may regulate serotonergic neurotransmission -Major depression
associated with ↑ pro-inflammatory cytokines, and eicosanoids.
Inducers of rapid tolerance disrupt lipid rafts.
ST JOHNS WART Studies in Europe suggest similar activity to TCAs in the treatment of minor depression
Adhd: primarily characterized by a persistent pattern of inattention and/or hyperactivity- impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development (criterion a) Prevalence 3-7 % school age children in usa and canada. High comorbidity (50-60%) with odd, ocd, depression, anxiety, 25-30% have learning disabilities, 60% diagnosed as children -symptoms persist into adulthood. Disorder, schizophrenia or other psychotic disorder, and must not be better explained by another mental disorder (mood, anxiety, dissociative, personality) criterion e. Adhd combined type six or more symptoms of inattention with six or more symptoms of hyperactivity-impulsivity for at least 6 months. Adhd- predominantly inattentive type six (6) or more symptoms of inattention but fewer than six of hyperactivity-impulsivity for at least 6 months. Adhd- predominantly hyperactive-impulsive type six (6) or more symptoms of hyperactivity-impulsivity but fewer than six symptoms of inattention.