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NUTR 4320 (4)
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ADHD.docx

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Department
Nutrition
Course
NUTR 4320
Professor
Kelly Meckling
Semester
Winter

Description
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 Diagnostic Criteria: 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. MEDICATION 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% of patients. 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 function 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 ADHD-- 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 improved. 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 symptomatology, while methylphenidate treatment may exert its therapeutic effect in ADHD through increasing DHEA levels. · 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. THERAPIES: 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 =hypertensive crisis. 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: reuptaketime 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 US and other countries show little to no effectiveness
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