Background
Pharmacological and behavioral treatments for Major Depressive Disorder (MDD) show
only modest efficacy. For instance, serotonin reuptake inhibitors (SRIs) produce response in
fewer than 60% who complete a full course of SRI pharmacotherapy. These medications
are not always well tolerated; in randomized controlled trials (RCT), ∼30% of subjects who
begin treatment with SSRIs or tricyclic antidepressants (TCA) drop-out. Thus there is a
continued need for the development of both better and better-tolerated pharmacological
interventions for MDD.Fatty acids are essential components of cell membranes. Unsaturated fatty acids have one or
more double-bonds between carbon atoms; when the double bond is in position 6 the
unsaturated fatty acid is called an “omega-6 fatty acids” while those with a double bond in
position 3 are “omega-3 fatty acids”, examples of which are eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA). In the Western diet omega-6 fatty acids or their
precursors (e.g. linoleic acid) are much more abundant than omega-3 fatty acids or their
precursors (e.g. alpha-linolenic acid). A high omega-6 to omega-3 ratio can alter cell
membrane properties and increase production of inflammatory mediators because
arachidonic acid, an omega 6 fatty acid found in cell membranes, is the precursor of
inflammatory eicosanoids, such as prostaglandins and thromboxanes. By contrast, omega-3
fatty acids are anti-inflammatory. Therefore, a high dietary omega-6 to omega-3 fatty ratio
could promote neuroinflammation. Increased omega-3 fatty acids concentration in the diet
may also act by altering CNS cell membrane fluidity and phospholipid composition which
may alter the structure and function of the proteins embedded in it. By this mechanism,
increased omega-3 fatty acid concentrations in cell membranes have been shown to affect
serotonin and dopamine neurotransmission.