Dr. Andrew Stoll - Omega 3 Fatty Acids

Andrew Stoll presented right after Paul Hardy. You may want to review that article too to round out the information. Karen.

Dr. Andrew Stoll talk - Omega 3 Essential Fatty Acids

Side 1. Andrew 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
- Childhood psychotic disorders
- General medical conditions
Notes: There are many variations in each of these.

Slide 4. Autism Co-morbidity
- Bipolar disorder
- Major depression
- Seizure disorders
- Obsessive-compulsive disorder
- Motor tics
- Learning disability
- Dyslexia
- Tuberous sclerosis
Notes: Many of the symptoms have a nutritional basis. The parents must bring the information to the doctors. You will need to be in

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 breast milk – 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 transudation
-Alternating 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 Transudation
-The receptor is the door to the cell
-The neurotransmitter knocks on the door
-Signal transudation converts and amplifies this extra cellular 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 Status 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 depokate, 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
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

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
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)
-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
-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)
-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)
-No controlled data in neuropsychiatric 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 oil, 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)
-Impaired platelet function (theoretical risk of bleeding only; weaker than aspirin)
-Contamination with heavy metals, or organ chlorine 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)

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 differ 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 receiving the "active" drug.
-This is where major discoveries are made
-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 Preliminary "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
-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-

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 Andrew Stoll.

Submitted by Karen from the autismandenzymes  Yahoo Group.