Bipolar Illness strikes approximately 5.7 million adults in the United States, or about 1–2% of the adult population in any given year 
. Importantly, the lifetime prevalence of suicide attempts in bipolar patients is over 30% 
, making uncontrolled bipolar disorder a large risk factor for suicidal behavior. In spite of the plethora of medications used to manage bipolar disease, including 60 years of clinical use of lithium, the majority of treated bipolar patients have “less than a satisfactory outcome” 
Several potential risk factors have been linked to suicidal behavior. Two of these include personality factors and PUFA serum levels. It is unknown whether PUFA serum levels are associated with personality factors and if these may interact to affect suicidal behavior. However, several studies suggest that low serum n-3 PUFA associate with aggressive and violent behavior. For example, n-3 PUFA have been found to be lower in suicide attempters 
and violent suicides correlate with seasonal variation in n-3 intake 
. Also, serum n-3 PUFA levels predict serotonin and dopamine metabolites in cerebrospinal fluid that differ between violent and non-violent subjects 
Supplementation with the long-chain n-3 (n-3) fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), either as stand alone or adjunctive therapies have shown efficacy in the treatment of bipolar disorder. However, results across studies are inconsistent and the role of n-3s in the treatment of bipolar disorder is unclear. A 2008 review by Turnbull et al. surveyed clinical trials that used n-3s to treat bipolar disorder 
. From over 100 publications, seven high quality and well-controlled trials were identified, of which four found positive mood improvements, two found no mood improvements and one did not report on mood improvements following n-3 supplementation. Therefore, while data is promising there remains ambiguity in the field. One factor not considered in the trials to date is the concentration of n-6 (n-6) fatty acids, which play complex physiological roles in both health benefit and pro-inflammatory state and are known to compete with n-3 fatty acids in many cellular processes, and therefore should be considered.
Evidence for the involvement of n-3 and n-6 fatty acids in bipolar disorder comes from several related lines of investigation. First, epidemiological studies have pointed to an association between n-3 and n-6 dietary intake and lifetime prevalence of bipolar disorder. Populations that consume greater long-chain n-3s and less long chain n-6s have a lower incidence of bipolar disease 
. Second, animal studies have shown that diets deficient in n-3s alter monoamine systems in limbic structures known to control mood (reviewed by Chalon 
), which provides a possible mechanistic link to psychiatric disorders. Third, mood stabilizers commonly used to treat bipolar disorder specifically inhibit membrane turnover and downstream signaling of the n-6 fatty acid, arachidonic acid (AA), but not the n-3, DHA 
. Both lithium and carbamazepine decrease expression of phospholipase A2, responsible for cleaving AA from the membrane. Additionally, lithium, carbamazepine, valproate and lamotrigine inhibit COX2 expression, responsible for processing AA into the prostaglandin E2 series signaling molecules. These data suggest that mood stabilizers tip the scales in the direction of n-3 activity, by inhibiting AA function and reducing competition with DHA and EPA. Furthermore anti-depressants that increase AA activity in rodents (e.g. imipramine), have a higher probability of inducing mania in human bipolar subjects 
. These data are consistent with the hypothesis that low n-3 or high n-6 tissue concentration may destabilize mood and suggest that the tissue balance between competing n-3 and n-6 fatty acid species may play a role in the pathoetiology of bipolar disorder.
The n-3 and n-6 PUFA are essential in the diet, since they cannot be synthesized de novo
by mammals. Technically, we only need to obtain the n-3, alpha linolenic acid (ALA), and the n-6, linoleic acid (LA), from dietary sources to synthesize longer chain n-3 and n-6 lipids from those (). However, studies have shown that humans are inefficient at converting short to long chain fatty acids and thus the tissue composition of all n-3 and n-6 lipids partially reflects dietary consumption 
. Single nucleotide polymorphisms (SNPs) in fatty acid desaturase (FADS) genes, partially responsible for metabolic inter-conversion, influence n-3 and n-6 serum levels as well 
, defining a diet x gene interaction in the control of fatty acid serum profiles and, potentially, factors related to psychiatric illness.
Schematic of biosynthetic pathway for common n-3 and n-6 fatty acids.
Following absorption, n-3 and n-6 fatty acids compete with each other for esterification and incorporation into cellular membranes, where they can affect the local microenvironment. In neurons, higher concentrations of DHA increase membrane fluidity and receptor kinetics 
. The n-3, EPA, and the n-6, AA, also compete with each other for processing to various eicosanoids, which often have opposing physiological functions relative to immune inhibition or activation, respectively. Furthermore, the activity of the FADS1, FADS2 and elongase enzymes (depicted in ) can also control the available pools of short chain or long chain fatty acids, providing a level of competition within each of the n-3 or n-6 classes as well.
Therefore, to fully understand the efficacy of n-3 and n-6 fatty acids in bipolar depressive illness we will need an understanding of the subjects' complete lipid profiles and the ratios between competing lipids and their possible influence on various burdens of disease. The current report explores the relationship between PUFA profiles and personality factors, which themselves have associated with bipolar disorder and global functioning in bipolar subjects (
). We analyzed plasma profiles of n-3 and n-6 fatty acid species in 27 well-characterized bipolar subjects and determined association with personality factors and suicidal history.
Given prior literature discussed above that n-3 intake inversely associates with violent behavior and suicidality, we hypothesize that serum levels of the long chain n-3s, DHA and EPA, may positively associate with personality factors that may be protective against suicide behavior and/or negatively associate with personality factors that, themselves, associate with increased risk of suicide behavior. We also hypothesize that the n-6s, linoleic acid and arachidonic acid, may modify the relationship between n-3s and psychiatric measures and that physiologically relevant ratios on n-3s and n-6 may be important to consider in the analyses.