Alternative Medicine Review 2007 (Sep); 12 (3): 207–227 ~ FULL TEXT
University of California, Berkeley, California, USA
The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are orthomolecular, conditionally essential nutrients that enhance quality of life and lower the risk of premature death. They function exclusively via cell membranes, in which they are anchored by phospholipid molecules. DHA is proven essential to pre- and postnatal brain development, whereas EPA seems more influential on behavior and mood. Both DHA and EPA generate neuroprotective metabolites. In double-blind, randomized, controlled trials, DHA and EPA combinations have been shown to benefit attention deficit/hyperactivity disorder (AD/HD), autism, dyspraxia, dyslexia, and aggression. For the affective disorders, meta-analyses confirm benefits in major depressive disorder (MDD) and bipolar disorder, with promising results in schizophrenia and initial benefit for borderline personality disorder. Accelerated cognitive decline and mild cognitive impairment (MCI) correlate with lowered tissue levels of DHA/EPA, and supplementation has improved cognitive function. Huntington disease has responded to EPA. Omega-3 phospholipid supplements that combine DHA/EPA and phospholipids into the same molecule have shown marked promise in early clinical trials. Phosphatidylserine with DHA/EPA attached (Omega-3 PS) has been shown to alleviate AD/HD symptoms. Krill omega-3 phospholipids, containing mostly phosphatidylcholine (PC) with DHA/EPA attached, markedly outperformed conventional fish oil DHA/EPA triglycerides in double-blind trials for premenstrual syndrome/dysmenorrhea and for normalizing blood lipid profiles. Krill omega-3 phospholipids demonstrated anti-inflammatory activity, lowering C-reactive protein (CRP) levels in a double-blind trial. Utilizing DHA and EPA together with phospholipids and membrane antioxidants to achieve a triple cell membrane synergy may further diversify their currently wide range of clinical applications.
From the Full-Text Article:
The long-chain omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are conditionally essential nutrients now established to enhance life quality and lower the risk of premature death. They are orthomolecules whose functional sites are exclusively cell membranes, wherein they are structurally and functionally integrated via phospholipid
molecules. Their confirmation as efficacious cardiovascular protectants has spurred research into their benefits for the human brain. This review focuses on their clinical roles in cognition, behavior, and mood and on their potentially synergistic interactions with the cell membrane phospholipid nutrients.
Adequate dietary availability of DHA and EPA is fundamental to brain function. DHA/EPA are important throughout adulthood, as well as during the brain growth spurts that characterize prenatal and postnatal development. Dietary supplementation with DHA and EPA has proven beneficial for many of the known higher mental functions.
Among the proven brain benefits of DHA/EPA are the perinatal development of visual and other sensory functions; perinatal emergence of cognitive function and
maintenance throughout life; behavior management; and mood control (e.g., the mood swings of bipolar disorder or symptoms of major depressive disorder [MDD]). The substantial clinical evidence that supports these applications is discussed in the sections that follow.
Omega-3s in Childhood Brain Development
During the last trimester of fetal life and the first two years of childhood, the brain undergoes a period of rapid growth – the “brain growth spurt.”  Nutrient insufficiency during this period can compromise brain function. DHA is one nutrient absolutely required for the development of the sensory, perceptual, cognitive, and motor neural systems during the brain growth spurt. [1,2] EPA’s importance for the brain’s development in utero is unclear, but colostrum and breast milk contain EPA, albeit in lesser amounts than DHA. [3,4]
The fundamental importance of DHA for brain development is beyond dispute.  The neurons are continually forming axons and dendritic extensions
with accompanying cell membranes. Growing membrane must be relatively fluid, and DHA is the most fluidizing element in cell membranes (discussed later
in this review). Even the synapses that are the primary functional units of brain circuits are made from membranes preferentially enriched in DHA. 
The retina, functionally an extension of the brain, contains rods and cones with the most fluid membranes of all the body’s cell types; they are also
highly enriched in DHA. Laboratory animals (rodents, primates) with experimentally induced omega-3 deficiencies show deficits in retinal structure, visual acuity development, and cognitive performance. [6-8]
Perinatal Importance of DHA and EPA
Demand for DHA rises exponentially as the brain rapidly expands in the third trimester, and continues after birth as the baby interfaces with environmental
stimuli. Infants born prematurely are at special risk for omega-3 insufficiency because they may not have benefited from a full trimester of the mother’s
lipid stores. Preterm infants have very limited ability to synthesize DHA from the shorter chain alpha-linolenic acid (ALA; C18:3). 
After birth, omega-3 status depends on the infant’s innate lipid metabolism and dietary intake of breast milk or formula. Although DHA and EPA are prominent ingredients of breast milk, many infant formulas do not contain these nutrients. Supplementing the mother’s diet with ALA is not a reliable means for obtaining DHA. In one study, lactating mothers received 10.7 g/day of ALA from flaxseed oil for four weeks. Breast milk levels of ALA, EPA, and DPA (docosapentaenoic acid; C22:5 omega-3) increased, but not that of DHA. 
All infants, whether preterm or full term, seem to require dietary DHA for retinal development and normal visual function. A meta-analysis evaluated studies
on visual resolution acuity differences in healthy preterm infants, either supplemented or not supplemented with DHA.  Four prospective trials were included, providing data from both behavioral acuity tests and visual evoked potentials. Intake of DHA was correlated with significantly better visual resolution acuity at ages two months and four months. In another meta-analysis, this same research group found an advantage of DHA intake in full-term infants up to four months post-birth. 
McCann and Ames published an extensive review of the evidence that DHA is important for the development of cognition and other normal brain functions.
 Their 258 references included meta-analyses, randomized controlled trials (RCT) on cognitive and behavioral performance, studies with rodents and nonhuman primates, and breastfeeding studies. Within the limits imposed by performance testing of infants and toddlers, they concluded that:
In animals whose brain concentrations of DHA were severely reduced, dietary supplementation with DHA restored control
Studies with human infants suggest supplementation with DHA in formula or by boosting maternal levels enhances neuromotor development.
Application of a wide range of tests yielded a positive association between breastfeeding and infant mental performance.
Although it is difficult to test cognitive performance within the first year, infants who were fed breast milk or formulas with DHA were found (within a few
months after birth) to have superior visual acuity compared to those fed less than adequate DHA. This superior visual function persists through the first year after birth  and perhaps into the seventh year or later. 
Treating Developmental Coordination Disorder/Dyspraxia
The importance of DHA/EPA for overall brain and motor development after birth is illustrated by dyspraxia, also known as developmental coordination disorder
(DCD). DCD/dyspraxia involves specific impairments of motor function and seriously affects about five percent of school-aged children.  DCD’s core motor
deficits are often accompanied by difficulties with learning, behavior, and psychosocial adjustment that overlap with dyslexia and attention deficit/hyperactivity disorder (AD/HD) and often persist into adulthood.
A double-blind RCT was conducted on 117 children ages 5-12, using a mixed omega-3/omega-6 supplement versus an olive oil placebo.  The supplement
was 80-percent fish oil and 20-percent evening primrose oil, with a 4:1 omega-3 to omega-6 ratio. The total daily dose provided 174 mg DHA, 558 mg EPA,
and 60 mg omega-6 gamma-linolenic acid (GLA), plus 9.6 mg d-alpha tocopherol. Although the trial found no significant improvement in motor skills after three
months, the researchers did report significant improvements in other areas.  The children who received the omega-3/omega-6 supplement showed three times the normal expected gain in reading skills and twice the normal gain in spelling competency, plus marked improvement in behavior. The children who received the olive oil placebo were switched to the omega-3/ omega-6 supplement after three months and after three more months showed similar “catch-up” gains.
Other developmental brain disorders in children such as AD/HD and dyslexia overlap with DCD/ dyspraxia and are also linked to apparent DHA/EPA
deficits. Many of these children respond to oral supplementation of these nutrients, often administered with other nutrients as part of a comprehensive management regimen. [14,15]
Managing Attention Deficit/Hyperactivity Disorder
AD/HD is the most common childhood developmental disorder, with prevalence estimates ranging from 4-15 percent for school-age children in the United
States and elsewhere (see Richardson, 2006 for a recent review ). Often AD/HD persists into adulthood. Considerable damage to the individual, family, and society can be exacerbated by co-morbidity with many other disorders of behavior, learning, or mood. [14,16] AD/HD children consistently exhibit abnormal fatty acid status. 
Several studies have reported reduced blood concentrations of highly unsaturated fatty acids (FAs) in AD/HD children compared to controls (reviewed
by Richardson ). Typically, reductions have been found in DHA and total omega-3 FAs and in the omega-6 arachidonic acid (AA),  some of which may persist into adulthood.  In one study that included both AD/HD and non-AD/HD boys, low omega-3 levels were associated with a range of behavioral and learning problems, irrespective of the clinical diagnosis.  Whereas low blood omega-6 levels tend to correlate with some physical deficiencies, but not with cognitive or behavioral impairments, omega-3 deficiencies correlate with behavioral problems (conduct disorder, hyperactivityimpulsivity,
anxiety, temper tantrums, sleep difficulties) and learning difficulties in children. Thus Richardson, in her insightful review, emphasized, “…omega-3 status
is likely to be more relevant to AD/HD and related behavioral disorders.” 
Clinical evidence from controlled trials, open studies, and case reports has yielded mixed results from DHA/EPA supplementation in AD/HD and its comorbid
conditions. In 2001, a double-blind RCT of omega-3 FAs was conducted on AD/HD children.  The 63 children ages 6-12 years were said to be receiving
effective and stable treatment with stimulant medication, so this was an “add-on” study. They received daily adjunctive treatment of 345 mg pure DHA (from algae) or placebo. At the end of the four-month study, no changes were found on behavioral ratings or measures of inattention and impulsivity.
Similar negative findings came from a two month, double-blind RCT of 40 AD/HD-type children ages 6-12 years in Japan.  Children were randomized
to receive either omega-3 fortified foods (providing approximately 510 mg DHA and 100 mg EPA per day) or indistinguishable control foods containing olive oil. Although no differences emerged on various cognitive tests, combined teacher and parent ratings found a greater reduction of aggression in the DHA group. 
A third double-blind RCT was conducted at Indiana’s Purdue University on children with primarily AD/HD-type difficulties.  Fifty children (average
age 10 years) were randomized to receive either an omega-3/omega-6 formula from fish oil plus evening primrose oil (each daily dose supplying 480 mg DHA,
80 mg EPA, 96 mg GLA, and 40 mg AA, plus 24 mg alpha-tocopheryl acetate) or an olive oil placebo for four months. Significant benefits were found for attention and behavior and on clinical ratings of oppositional defiant disorder.
In 2002, Richardson and Puri published a double-blind RCT of 29 United Kingdom children with a primary diagnosis of dyslexia and secondary AD/HD-type symptoms.  Half the children received an omega-3/omega-6 combination with 480 mg DHA and 96 mg GLA as in the Purdue formula above, but with EPA higher at 186 mg, AA slightly higher at 42 mg, the omega-6 cis-linoleic acid at 864 mg, 60 IU vitamin E as dl-alpha tocopherol, and 8 mg thyme oil. The other half of the children received an olive oil “placebo” for three months. The omega-3/omega-6 combination produced significantly greater benefits than the olive
oil for inattention, anxiety/withdrawal, and disruptive behavior. The authors noted the olive oil placebo could have contributed some benefit and that use of a truly inert placebo might have yielded a better overall trial outcome.
The shorter-chain ALA may not be as effective for AD/HD as DHA/EPA plus GLA. Thirty adults with AD/HD were randomized to supplementation with a large dose of 60 g/day of flaxseed oil, olive oil, or fish oil.  Serum phospholipid fatty acid status was determined at baseline and 12 weeks. Although flaxseed
oil supplementation increased ALA levels of blood phospholipids, levels of EPA, DHA, and other omega-3 fatty acids were not increased; fish oil predictably
increased EPA, DHA, and total omega-3s.
Thus, it appears a mix of DHA, EPA, and omega-6 fatty acids (GLA and AA) can improve the attention, learning, and behavioral afflictions typical
of AD/HD, as well as co-morbidities such as anxiety/withdrawal, dyslexia, and aggression. There are numerous reports of low plasma and/or RBC omega-3 levels
in AD/HD children and adults.  Recently, a specific gene polymorphism was discovered that is linked to clinical AD/HD and features suboptimal functioning
of fatty acid desaturase enzymes.  Figure 1 illustrates the biosynthesis of the primary omega-3 and -6 fatty acids.
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