ExtraDAN: Dr. Stoll - Omega 3 Fatty Acids

[Guest guest]

This is the last speaker talk for me to review. Stoll

presentated right after Hardy. You may want to review that

article too to round out the information. .

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Dr. Stoll talk - Omega 3 Essential Fatty Acids

Side 1. Stoll – Omega 3 Fatty Acids in Autism

Psychopharmacology Research Laboratory

McLean Hospital

Harvard Medical School

Notes: Decades ago, many arthritics could get relief from essential

fatty acid and cod liver oil. Omega 3 EFA will be a key piece to

AS. Omega 3s are needed for every system in the body and are key to

many areas such as ADD, depression, schizophrenia,…It used to be

fish oils were called snake oils.

Slide 2. Autism Defined

- Autism is a biological syndrome, at least partially genetically

based.

- Autism may be more than 1 disorder.

- 80% of kids with autism also exhibit learning disabilities.

- Concept of autism still evolving.

- Autism is a " spectrum disorder "

- More adults are being diagnosed with " autism spectrum disorder "

Notes: Autism is a biological syndrome, at least partially

genetically based _ genetic subtypes

Autism may be more than 1 disorder – a new lingo is that people are

on spectrum disorder

80% of kids with autism also exhibit learning disabilities

Slide 3. Autism: Differential Diagnosis

- Asperger syndrome

- Rett's disorder

- Childhood disintegrative disorder

- PDD-NOS

- Childhood psychotic disorders

- General medical conditions

Notes: There are many variations in each of these.

Slide 4. Autism Co-morbidity

- Biopolar disorder

- Major depression

- Seizure disorders

- Obsessive-compulsive disorder

- Motor tics

- Learning disability

- Dyslexia

- Tuberous schlerosis

Notes: Many of the symptoms have a nutritional basis. The parents

must bring the information to the doctors. You will need to be in

charge.

Slide 5. Autism: The Opioid Theory

-Early exposure to exogenous quasi-opioids

-Source is incompletely digested gluten or casein, which form opioid-

like peptides in the gut

-Genetic vulnerability vs acquired forms (such as candidiasis)

-Failure of:

---–Intestinal enzymes (peptidases

-----Mucosal barrier (defective sulphation)

-----Blood-brain barrier

Notes: The opioid theory makes good sense for many cases, definitely

not all

[his slide included 2 references]

Slide 6. Autism: Inflammatory Bowel Theory

-High rates of inflammatory bowel disease are observed in autism

-Lymphoid hyperplasia (at the ileo-cecal junction)

-Biopsy revealed measles or mumps infection

-1/3 cases occurred immediately after immunization

-The proportion of patients with an inflammatory gastrointestinal

process as the etiology of their autism is unknown.

[includes 2 references]

Slide 7. Autism: Secretin Theory

-Pancreatic enzyme that activates peptidase

-Supportive open-label case reports

-The Allopathic medical establishment rejects the use of secretin in

autism

-Despite 5 negative placebo-controlled trials (some highly flawed),

secretin remains highly popular

-Future studies should focus on possible sub-groups that are

responsive to secretin.

[includes 2 references]

Slide 8. Autism: The Amygdala Theory

-The amygdala is a limbic system brain structure involved in " social

intelligence, aggression, and other behavioral processes

-The Kluver-Bucy syndrome (bilateral amygdala destruction in

animals) resembles some behaviors seen in childhood autism

-Functional MRI studies reveal lack of appropriate amygdala

activation in children with autism, when trying to determine the

emotions in photographs of human faces

Notes: Secretin interacts with receptors in this area of the brain.

[includes 1 reference]

Brain Imaging Findings

Slide 9. Autism Brain Imaging Findings

-Studies limited by small sample sizes and lack of replication

-2 replicable findings:

---enlarged temporoparietal regions: These regions are important for

auditory processing, recognition of emotions in others and many

other functions.

---Reduced size of posterior corpus callosum: Impairs communication

between left and right brain.

[includes 1 reference]

Slide 10. Omega3 Deficiency in Autism: Indirect Evidence

-Reduced frequency and shorter duration of breastfeeding in autistic

children compared to their normal siblings [two references for this]

-Abnormal heart rate variability [1 reference]

-High rates of stereotyped behaviors in omega-3 deficient rhesus

monkeys [1 reference]

Notes: We need the official studies, but ok to keep using it (omega-

3 fatty acids) in the meantime until they get around to the studies.

Slide 11. Evidence for Omega Deficiency in Autism

-High rate of inflammatory bowel disease.

-Supportive open-label data

-Increasing prevalence of autism over time??

-Are cross-national rates of autism negatively correlated with fish

consumption??

Needed: 1) Double-blind, placebo controlled studies. And 2) Oral vs

IV

Notes: Countries that have diets higher in Omega 3s such as eating a

large amount of fish, have lower rates of depression and other

disorders. The increase in autism spectrum in our country may be

related to our diet.

Slide 12. Eicosapentanoic acid (EPA 20:5:n3)

Major Omega-3 Fatty Acid in Fish Oil

Notes: This slide showed the structure of EPA. It said the multiple

double-bonds produce a kinked and flexible molecule and the first

double-bond begins at 3rd carbon from methyl (end of the fatty acid

chain). He said that having double-bonds keeps the molecule flexible

and this keeps it fluid in the body under different conditions.

Notes: What is an Omega 3 fatty acid? Poly means many double bonds.

The multiple double-bonds produce a kinked and flexible molecule.

Lard or solids have no double bond. The liquid oils will be liquid

at room temperature (in your body). Flax Seed Oil = EPA. DHA had the

focus for a long period of time – it is in breastmilk – but it is

proving to not be effective in working in clinical trials with

depression, bipolar, etc. has much slower turnover in the body

Slide 13. Eicosapentanoic acid

Many possible mechanisms of action

-Alteration in eicosanoid and cytokine pathways

-Reduction of abnormal signal transduction

-Alternatin in membrane order ( " fluidity " )

-Altered receptor function

-Pan-agonists at nuclear receptors (PPAR)

Notes: Many doctors need double-blind data to feel that this

approach is reasonable.

They pursued EPA as an alternative to lithium, depokate…which saved

lives before but came at a high cost. They have learned more about

the pathways and science has improved.

Slide 14. Signal Transduction

-The receptor is the door to the cell

-The neurotransmitter knocks on the door

-Signal transduction converts and amplifies this extracellular

membrane event into useful information within the cell

Notes: Use EPA and has rapid turnover in the body

Slide 15. Omega-3 Fatty Acids in Bipolar Disorder: Study Design

-Double-blind placebo-controlled 4-month trial

-N=30 bipolar outpatients (mostly Type I)

-All subjects had mania/hypomania within past 1 year

-Randomized to 9.6 g/day omega-3 vs placebo (olive oil)

-Concomitant meds left unchanged-N=8 entered study on no other drug

therapy

-Main outcome measures:

---Recurrence or lack or response

---SCID Stutus at end of trial

Notes: Bipolar Disorder:

½ got omega 3 and ½ got olive oil

Doing a perfect study is very difficult – fish oil smells so people

would know they did not have olive oil. One person's cat attacked

when the supplement was brought out.

Slides 16-17. Two line graphs showing the results.

Notes: The omega 3 patients did great, 12 out of 14 did response to

the treatment. The olive oil patients dropped especially by the

second month. Because the placebos were dropping out at such a rate,

by the fourth month they stopped instead of going on to the 9 month

target date because they were running out of placebos. The response

shown gave results stronger than lithium and deprokate, but these

results may not replicate as dramatically. Omega 3 are anti-

psychotic agents. At the moment, these should not be relied upon

exclusively – but used as an adjunct therapy. They found that it is

EPA and not DHA that is helpful.

Slide 18. Omega-3 Fatty Acids in Unipolar Depression

Evidence

1. 4 studies reported lower blood omega-3 fatty acids (usually

EPA) in patients with major depression.

2. Epidemiological evidence pints to lack of omega-3 fatty

acids as world-wide risk factor for depression.

3. The neurochemical effects of omega-3 depletion are

consistent with models of depression.

4. Abnormalities in the omega-3 dependant eicosanoid and

cytokine pathways are present during major depression.

5. Open-label case series reporting antidepressant effects.

6. Double-blind data reporting the antidepressant effects of

fish oil in bipolar disorder.

7. Reduced rates of seasonal mood shifts in Iceland and Japan.

Slide 19. Evidence for Omega 3 Depletion in Western Diet

-Rates of major depression & cardiovascular disease inversely

correlated with fish consumption.

-Outcome in schizophrenia better in high fish consuming nations.

-The increased incidence of major depression in the 20th century is

directly correlated to a drop in omega-3 consumption.

[included 4 references]

Notes: Schizophrenia patients in other countries did much better

than in the US because of their diet. Also correlates well with

depression in other countries – the more fish one eats the less

depression there is. Post-partum depression – also a strong reaction

because women give omega 3s to baby through the placenta

Slides 20-21. Two graphs showing data supporting points in previous

slide.

Slide 22. Omega-3 Fatty Acid Depletion in Post-partum Women

After 1 child: low DHA

After 2 children: Lower DHA

After 3 children: Lowest DHA

Triplets > twins

Triplets

Lactation: At 16 weeks, decreased DHA

Notes: Shows that the Omega-3 are depleted with child bearing and

the number of children.

Slide 23. Picture of Eskimo ice fishing.

Notes: Because fish has mercury you need to get omega 3 from other

sources.

Slide 24. 5 pictures of phytoplankton (algae)

Notes: Fish do not make omega 3 they get it from the phytoplankton

they eat through the food chain. So try to eat the other sources

directly.

Slide 25. Natural Sources of Omega-3 Fatty Acids

Slide 26. Fish with High Omega-3 Content

Chart showing quantities of DHA and EPA in different fish

Omega-3 content of fish varies geographically and from year to year

due to climatic effects of algae and other factors.

[included 1 reference]

Slide 27. Terrestrial Sources of Omega-3 Fatty Acids

Fish with high omega 3 content – fish sources will vary

Perilla Oil

Chia

Borage seed oil

Flax seed oil good but there are some drawbacks

Wild game because they eat wild food – not grain fed

Seaweed has DHA and EPA but not a good source and can have heavy

metals

Omega 3 Eggs available in grocery, they are fed a special feed to

increase fatty acid content

Slide 28. Effect of Regional Diet on Mercury Levels Among Greenlander

Graphs showing that in North Greenland where there is high local

fish consumption they have a much higher level of mercury in the

system than Greenlanders living in Denmark where there is less fish

consumption.

Slide 29. Palmitic Acid

-a saturated fat

-need a little bit but don't eat a lot

-no double bonds makes it a rigid solid that does not function well

in cells

Palmitic acid is an 18 carbon saturated fat. Note that the lack of

double bonds produces a straight chain molecule. This straight chain

structure is rigid, which is why palmitic acid and other saturated

fats (such as lard) are solid at room temperature (a high melting

point). In contrast, the multiple double bonds in polyunsaturated

fats, such as the omega-3 fatty acids, produce a very flexible

molecule, which is liquid oil) at room temperature (low melting

point).

Slide 30. Alpha-linolenic acid

–double bonds helps keep it a liquid

An 18 carbon omega-3 fatty acid with 3 double bonds. Alpha-linolenic

acid is found in flaxseed and other plant oils. Note how just 3

double-bonds alters the chemical structure, making alpha-linolenic

acid much more highly folded than an 18 carbon saturated fat.

Slide 31. EPA

EPA is a 20 carbon omega-3 fatty acid with 5 double-bonds. Note the

highly kinked structure of this polyunsaturated fat, which is found

in high concentration in certain fish oils. EPA directly competes

with its omega-6 counterpart, arachadonic acid, in many biochemical

pathways. Arachadonic acid is converted into highly inflammatory

compounds (eicosanoids), which are crucial in certain conditions,

but if arachadonic acid activity is unchecked, the inflammatory

process can lead to many different disease states. EPA forms only

mildly inflammatory compounds. These weaker EPA eicosanoids, along

with EPA's inhibition of arachadonic acid conversion into the highly

inflammatory eicosanoids produces many health benefits, including

reduced rates of heart attack, less inflammatory disease, such as

rheumatoid arthritis, and reduced depressive illnesses.

Slide 32. DHA

DHA is a 22 carbon omega-3 fatty acid with 6 double bonds. Certain

fish oils are rich in DHA. Note the markedly kinked chemical

structure, which is characteristic of highly polyunsaturated fatty

acids. DHA is crucial for neurological and visual development in the

human fetus and newborn, and it found in high concentration in the

brain throughout life.

Slide 33. Arachidonic acid

Arachidonic acid is 20 carbon omega-6 fatty acid with 4 double

bonds. Omega-6 fats are polyunsaturated with the first double-bond

beginning with the 6th carbon atom from the methyl end of the

molecule.

Slide 34. Oleic acid

Oleic acid is an 18 carbon fat of the omega-9 class, because the

first and only double bond begins at the 9th carbon from the methyl

end of the molecule. It is considered monounsaturated because it has

only one carbon double-bond. Note that one double-bond between the

9th and 10th carbon atoms produces a slight kink in the chemical

structure.

Slides 35-36. diagrams showing the essential fatty acid metabolism

Omega-6 is LA goes to GLS goes to AA

Omega-3 is ALA goes to EPA goes to DHA

In order of carbon chain length and number of double bonds

Slide 37. Graphs showing the results demonstrate that EPA and DHA

supplementation alters brain structure, and supports the hypothesis

that omega-3s " fluidize " neuronal cell membranes.

Notes: These things really do change your body chemistry. Fat

content in the brain affects the water flow in the brain and

function – affects how stiff or fluid your membranes are.

Slide 38. Omega-3 Fatty Acids: Dosing Controversy

Replacing an omega-3 deficiency (low dose) vs Pharmacological effect

(high dose)

Notes: He thinks it is both.

Slide 39. Omega-3 Fatty Acids (Fish oil)

Advantages:

-Double-blind, placebo-controlled data (N-30) in bipolar disorder.

-well tolerated

-health benefits

-patient acceptance

-no weight gain - because they turn on fat metabolism systems

-Highly concentrated forms now available

Drawbacks:

-More efficacy data needed

-High-doses required

-Most currently available fish oils inadequate in potency

-GI distress at high doses – some comment on bleeding but only a few

isolated cases, nausea and diarrhea passes with time – side affects

-Fishy aftertaste which may be due to rancidity of fatty acids

through oxidation

-Theoretical risk of increased bleeding

Usage Guide: 2-5 grams of omega-3 (EPA+DHA BID

Caution: anticoagulants or high-dose ASA or NSAID

Note: Drug companies cannot patent these things – marketing,

research money, blah, blah, and that is why the natural substances

are not popular. Most fish oil is squished fish in a bottle – can go

rancid easily. Go with better quality oils. Any fish oil has been

distilled or concentrated to over 50% purity is pretty safe. Contact

the company and ask about the mercury and heavy metal content. If

they will not tell you, don't use that company

Slide 40. Flax Oil (alpha-linolenic acid_

Advantages:

-More palatable than fish oil

-Native flax oil more concentrated than native fish oil

-May be used in recipes (but not as a frying oil)

Drawbacks:

-No controlled data in neuropyschiatric disorders

-May cause more manic switch than fish oil

-Limited conversion to longer chain omega-3

Usage: 1 tablespoon (~7 g of ALA) qd-TID or use capsules. Omega-3

dosage with flax oil should be the same or higher as that used for

fish oid, due to the incomplete conversion of ALA to EPA.

Slide 41. Potential Adverse Effects: Fish oil

-Gastrointestinal disturbance

(benign and generally only seen at high dosage levels)

-Fishy aftertaste (repeat)

(due to rancidity of fatty acids through oxidation)

-Hypervitamosis A

(only if high-dose cod liver oil used)

-Imparied platelet function

(theoretical risk of bleeding oly; weaker than aspirin)

-Contamination with heavy metals, or organochlorine compounds

Slide 42. Ideal Characteristics of a Fish Oil Supplement

-Maximum concentration (>90% now available)

-No heavy metal or organic carcinogens

-No fishy aftertaste, smell, or " repeat "

(these unpleasant features can be prevented by encapsulating under

nitrogen to minimize oxidation)

-EPA>DHA

Slide 43. Usage Guide

-Fish oil preferred to flaxseed oil at this time.

-Usual dosage range: 1.5-10 g/d (3-5 g/d typical) omega-3 fatty

acids (EPA or EPA+DHA)

-Read labels carefully. Brands differe widely in omega-3 content

(listed by serving size, not per capsules)

-BID schedule optimal (qd, TID also ok)

-Food increases omega-3 absorption.

-Highest content of EPA desirable

-Antioxidants (such as vitamins C & E, etc) may prevent in vivo

degradation of omega-3s

-If GI is upset: Divide dose, ginger root, Daikon radish

-Caution: Xenical; anticoagulants or high-dose NSAID?

Notes: 2-5 grams of omega-3 once or twice daily, either EPA or

EPA+DHA, start low and go slow. A few problems with Flax seed oil –

prostate cancer. Flax Oil – is good inside the food such as baking

or pancakes, not for frying.

Slide 44. Phases of Medical Research

There are two ways things happen in science: 1) Scientific

hypothesis or 2) clinical observation. both go to preliminary open-

label or uncontrolled trial. Then go to Preliminary controlled

study, and then to Definitive controlled study.

Slide 45. The Importance of Preliminary " Open-label " or Uncontrolled

Studies

- " Open-label " means both the patient and clinician/researcher know

that the patient is receiveing the " active " drug.

-This is where major discoveries are made

-Inexpensive

-Huge, double-blind, placebo-controlled studies are crucial for

confirmation of initial findings

Notes: Most things in this area start by observation – what parents

notice or doctors notice from subsequent patients. If something is

harmless why not use it.

Slide 46. The Pitfalls of Prelijminary " Open-label " or Uncontrolled

Studies

-The observations may be the results of the " placebo effect "

-Many sources of bias can distort the results

-Must not over-interpret open-label trials

Slide 47. Many Sources of Bias Can Distort the Results

-Placebo effect

-Lack of systematic diagnosis

-Not counting " drop-outs "

-Unconscious or conscious fudging of the results

---The researcher wants the treatment to work

---The participant wants to please the researcher

Slide 48. The Importance of Scientifically Controlled Research

-Evaluates preliminary uncontrolled findings

-Permits other researchers to replicate methods

-Permits patients, families, and clinicians to evaluate the merits

and drawbacks of a new treatment

-Permits insurance companies, the FDA, and other regulatory agencies

to evaluate the merits and drawbacks of a new treatment

Slide 49. Omega-3s in Autism: A Research Agenda

Eventually you need controlled research

-Well designed placebo-controlled clinical trials

-Must answer the following questions:

---What is the best route of administration? Oral or IV

---What is the most effective omega-3? EPA, DHA, ALA, or some

combination?

---What is the optimal dosage?

-Funding sources

---The most difficult challenge

Notes: He said that eventually well designed studies are necessary

and must include looking at and trying to answer the questions

listed. Funding is difficult because it involved diet and nutrition.

Slide 50. Omega-3 Fatty Acids in Autism: Unanswered Questions

-Are omega-3s truly effective in autism?

-If so, which omega-3s is the active component (EPA, DHA, ALA or all

3?)

-What is the proper dosage?

-Oral vs IV?

-Are there biological markers that will predict omega-3 response?

-Are there subtypes of autism that preferentially respond to omega-

3s?

Slides 51-52. He recommends Coromega for younger kids and Omegabrite

for older people. These are safe bets. Showed book cover and web

site for Omegabrite and the book The Omega-3 Connection by

Stoll.