Fats and Factors: Lipid Profiles Associate with Personality
Factors and Suicidal History in Bipolar Subjects
Simon J. Evans1*, Alan R. Prossin1, Gloria J. Harrington1, Masoud Kamali1, Vicki L. Ellingrod2, Charles F.
Burant3, Melvin G. McInnis1
1Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, United States of America, 2School of Pharmacy, University of Michigan, Ann Arbor, Michigan,
United States of America, 3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
Polyunsaturated fatty acids (PUFA) have shown efficacy in the treatment of bipolar disorder, however their specific role in
treating the illness is unclear. Serum PUFA and dietary intakes of PUFA associate with suicidal behavior in epidemiological
studies. The objective of this study was to assess serum n-3 and n-6 PUFA levels in bipolar subjects and determine possible
associations with suicidal risk, including suicidal history and relevant personality factors that have been associated with
suicidality. We studied 27 bipolar subjects using the NEO-PI to assess the big five personality factors, structured interviews
to verify diagnosis and assess suicidal history, and lipomics to quantify n-3 and n-6 PUFA in serum. We found positive
associations between personality factors and ratios of n-3 PUFA, suggesting that conversion of short chain to long chain n-
3s and the activity of enzymes in this pathway may associate with measures of personality. Thus, ratios of docosahexaenoic
acid (DHA) to alpha linolenic acid (ALA) and the activity of fatty acid desaturase 2 (FADS2) involved in the conversion of ALA
to DHA were positively associated with openness factor scores. Ratios of eicosapentaenoic acid (EPA) to ALA and ratios of
EPA to DHA were positively associated with agreeableness factor scores. Finally, serum concentrations of the n-6,
arachidonic acid (AA), were significantly lower in subjects with a history of suicide attempt compared to non-attempters.
The data suggest that specific lipid profiles, which are controlled by an interaction between diet and genetics, correlate with
suicidal history and personality factors related to suicidal risk. This study provides preliminary data for future studies to
determine whether manipulation of PUFA profiles (through diet or supplementation) can affect personality measures and
disease outcome in bipolar subjects and supports the need for further investigations into individualized specific
modulations of lipid profiles to add adjunctive value to treatment paradigms.
Citation: Evans SJ, Prossin AR, Harrington GJ, Kamali M, Ellingrod VL, et al. (2012) Fats and Factors: Lipid Profiles Associate with Personality Factors and Suicidal
History in Bipolar Subjects. PLoS ONE 7(1): e29297. doi:10.1371/journal.pone.0029297
Editor: Bernhard T. Baune, University of Adelaide, Australia
Received June 29, 2011; Accepted November 24, 2011; Published January 13, 2012
Copyright: ? 2012 Evans et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This project was supported by grants from the Michigan Institute for Clinical Health Research to SJE, the National Alliance for Research in Schizophrenia
and Depression (NARSAD) Independent Investigator Award and National Institutes of Mental Health (NIMH) grant (R01 MH082784-01) to VLE, the Heinz C.
Prechter Bipolar Research Fund to MGM; and services and resources from the National Institutes of Helath- National Center for Research Resources (NIH-NCCR),
General Clinic Research Center (GCRC) Program (M01-RR-59 and UL1RR024986), the Chemistry Core of the Michigan Diabetes Research and Training Center
(NIH5P60 DK 20572), the Michigan Nutrition Obesity Research Center (DK089503) and the Washtenaw Community Health Organization (WCHO). The funders had
no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
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.
PLoS ONE | www.plosone.org1 January 2012 | Volume 7 | Issue 1 | e29297
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 (Figure 1). 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.
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
Figure 1) 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 ([15,16]). We analyzed plasma profiles of n-3 and n-6 fatty
acid species in 27 well-characterized bipolar subjects and deter-
mined 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 person-
ality 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.
In assessing the relationship between the five personality factor
scores and n-3, n-6 fatty acids, we found that the relative plasma
concentrations of several lipid species or physiologically relevant
ratios between lipid species significantly correlated with various
personality factors. Because of the pilot nature of this study,
multiple testing corrections were not applied, however, all test are
reported in Table 1. We found twice the number of significant
correlations, below the 5% type I error threshold, than would be
predicted by chance. However, independence of the tests cannot
be assumed and we found a clustering of significant findings of
associations between EPA (relative to it’s precursor and product)
and personality factor scores.
Figure 2 shows Pearson correlations revealing that the
ALA:EPA ratio negatively correlated and the EPA:DHA ratio
positively correlated with extraversion (p=0.045, r=20.389 for
ALA:EPA; p=0.048, r=0.384 for EPA:DHA) and agreeableness
(p=0.023, r=20.436 for ALA:EPA; p=0.024, r=0.433 for
Figure 1. Schematic of biosynthetic pathway for common n-3
and n-6 fatty acids. Major dietary inputs are shown with arrows and
enzymes catalyzing each conversion are given.
Lipids, Personality and Suicide Risk
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Table 1. Statistical Tests.
20.17 (20.22) 20.09 (20.02) 0.14 (20.04)
20.07 (20.23) 20.06 (20.04) 0.09 (0.31)
N (cor. df)
20.27 (20.21) 20.17 (20.14) 20.17 (20.15) 20.39 (20.32) 20.18 (20.14) 0.38 (0.28)
20.11 (20.13) 0.03 (0.12)
N (cor. df)
20.08 (20.07) 20.26 (20.24) 20.11 (20.22) 20.24 (20.30) 20.50 (20.51) 20.17 (20.16) 20.09 (20.03) 0.41 (0.41)
N (cor. df)
20.08 (20.07) 20.09 (20.14) 20.00 (0.04)
0.11 (20.03) 0.00 (20.08) 20.21 (20.15) 0.05 (0.12)
20.12 (20.14) 20.44 (20.41) 20.08 (20.04) 0.43 (0.39)
N (cor. df)
20.07 (20.01) 20.02 (20.13) 20.03 (20.03) 0.30 (0.11)
20.07 (20.04) 20.18 (20.12) 20.35 (20.33) 20.10 (20.34) 20.13 (20.15) 0.22 (0.29)
N (cor. df)
Factors: N, Neuroticism; E, Extraversion; O, Openness; A, Agreeableness; C, Conscientiousness
Correlations and p-values are shown in each box with corrections for age, BMI and antipsychotic dose shown in the parentheses. Significant correlations are bolded with those remaining significant after correction marked with an
Lipids, Personality and Suicide Risk
PLoS ONE | www.plosone.org3 January 2012 | Volume 7 | Issue 1 | e29297
EPA:DHA). These data suggest that a higher pool of EPA, relative
to its precursor, ALA, and its downstream product, DHA,
associate with extraversion and agreeableness. The correlations
with agreeableness remained significant following correction for
age, BMI and antipsychotic medication dose.
Figure 3 shows that the ALA:DHA ratio negatively correlated
with openness factor score (p=0.008, r=20.498) and FADS2
activity positively correlated with openness factor score (p=0.036,
r=20.406). These data suggest that more efficient conversion of
the 18 carbon ALA to the 22 carbon DHA (partially dependent on
FADS2 activity) may associate with increased openness to
experience. These data remained significant following correction
for age, BMI and antipsychotic medication dose (Table 1).
In an analysis that compared lipid species in bipolar patients
with and without a history of suicide, we found a significantly
lower serum AA concentration (p=0.026) and a trend for lower
EPA serum concentrations (p=0.070) in suicide attempters, as
shown in figure 4a. After correcting for age, BMI and
antipsychotic medication use, the difference in AA serum
concentration between the suicide attempters and non-attempters
remained significant (p=0.037).
Identifying metabolic or dietary factors that influence factors
associated with psychiatric illness may provide a path to improving
therapeutic tools. In previous studies, an effect of n-3 fatty acid
supplementation has shown inconsistent association with improve-
ments in bipolar symptomology () and we suggest that this may
be due to variable concentrations of other lipid species, either n-6
fatty acids that tend to compete with n-3 fatty acids in a variety of
signaling, inflammatory and other pathways; or genetically variant
enzyme activities that favor pooling one fatty acid over another. In
this report, we found that n-3 and n-6 lipid profiles correlate with
aspects of the five factor personality model that have themselves
been associated with suicidal behavior ([16,17,18]). This does not
imply a relationship between PUFA profiles and suicide. However,
given prior literature on such a potential relationship (), the
current study contributes to a warranting of further investigation
into the relationship between the various components of suicide
risk and PUFA profiles.
Without a control population in the current study, it is
impossible to state whether or not the association between PUFA
profiles and personality factors is specific to a psychiatric
population. However, this is not our purpose. If PUFA profiles
influence personality factors, like agreeableness and extraversion,
this may be one additional risk factor for suicidal behavior in
psychiatric patients, like bipolars, who are already at increase risk
for suicide. An association between PUFA profiles and personality
factors may also exist in a healthy population, but without
significant consequence. Larger studies with a control population
are necessary to answer these questions.
We also found associations between lipid profiles and suicidal
history in bipolar subjects. These data further support a link
between essential fatty acid metabolism and mood disorders.
While the current pilot study is an observational, cross-sectional
study, it raises important questions regarding potential causative
roles for lipid profiles in regulating personality phenotypes that
may impact the treatment of bipolar disorder. We are cognizant of
the fact that personality factors, promoted as trait markers in
bipolar disorder are not entirely stable  and longer-term
longitudinal studies are necessary to examine the relationship
between personality traits and fatty acid profiles.
In the current study, we found that DHA:ALA ratios and
FADS2 activity (which promotes DHA synthesis) significantly
correlated with openness personality factors, correlations that
Figure 2. Scatter plots of ALA:EPA ratio, EPA:DHA ratio and both agreeableness and extraversion factor scores. Graphs show
significant correlations between ALA:EPA and agreeableness (p=0.023, r=20.436) and extraversion (p=0.045, r=20.389) and significant positive
correlations between EPA:DHA and agreeableness (p=0.024, r=0.433) and extraversion (p=0.048, r=0.384).
Lipids, Personality and Suicide Risk
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remained significant following correction for age, BMI and
antipsychotic medication dose. These data suggest that the
conversion from short chain ALA to long chain DHA, which is
moderated by both dietary and genetic factors that control FADS1
and FADS2 activity, associate with openness, which itself is
positively associated with suicidal risk in bipolar subjects .
Therefore, this provides one point where dietary input and n-3
metabolism may interact to contribute to the regulation of
personality factors that influence suicidal behavior. Future
prospective studies are required to clarify whether there is a
causal role for dietary PUFA that can be manipulated to reduce
In support of this EPA:ALA and EPA:DHA ratios correlated
with agreeableness and this association also remained significant
following correction for age, BMI and antipsychotic medication
dose. Thus, a higher pool of EPA relative to its precursor ALA or
its product DHA, which would be promoted by lower FADS2
activity, associated with higher agreeableness factor scores.
Previously, higher agreeableness scores have been shown to be
protective against suicidal behavior .
Finally, we found that the long chain n6, AA, was lower in
subjects with a history of suicide attempt, suggesting that increased
serum concentrations of this PUFA may be protective. This is
consistent with prior literature associating suicidal behavior with
decreased serum lipids, including cholesterol, although this is
controversial . Higher AA pools would also be promoted by
lower FADS2 activity, since this enzyme promotes the conversion
of AA to longer chain lipids. These data may seem paradoxical
since one would expect the activity of the n-3 fatty acids, EPA and
DHA to be lower due to competition with increased AA. However,
in an analysis that looked at AA to DHA, AA to EPA and total n-6
to total n-3 ratios, we found that all of these ratios were higher in
subjects with a history of suicide, suggesting a complex relationship
between absolute and relative AA concentration as a risk factor for
psychiatric illness. These data are not presented because they did
not reach statistical significance, potentially due to the low power
of the current study.
Taken together, these data suggest that increased activity of
FADS2, which is genetically moderated with known SNP
variants that control serum lipid profiles , may increase
the risk of suicidal behavior in bipolar subjects. Referring to
figure 1, increased activity of FADS2 would reduce the pool of
both AA and EPA by promoting conversion to longer chain
fatty acids shown in both the n-3 and n-6 pathways. We found
the increased FADS2 activity and several consequences of
Figure 3. Scatter plot of openness factor score and (a) serum
ALA:DHA ratio or (b) FADS2 activity. Graphs show a significant
negative correlation between openness factor score and serum
ALA:DHA ratio (p=0.008, r=20.498) and a significant positive
correlation between openness factor score and FADS2 activity
Figure 4. Bar graph of differences in serum AA concentration
between subjects with and without a history of suicide
attempt. Serum AA is plotted for both suicide attempters and non-
attempters; error bars show standard deviation (p=0.026).
Lipids, Personality and Suicide Risk
PLoS ONE | www.plosone.org5 January 2012 | Volume 7 | Issue 1 | e29297
increased activity, including increased DHA:ALA, increased
DHA:EPA, decreased EPA:ALA and reduced AA serum
concentrations, all associated with markers of increased suicidal
risk, as discussed above. Interestingly, increased FADS2 gene
expression has been previously reported in the prefrontal cortex
of bipolar subjects , a brain region that influences mood
Limitations of this study include a small sample size, a
clinically diverse group (regarding current status and medication
history) and the lack of a healthy control group to make
comparisons, which all limit the statistical power of the study
and ability to extrapolate to a larger population. Furthermore,
the lack of multiple testing correction requires the data be
examined cautiously and the need for confirmation in larger
sample sets with the added power to analyze SNP variants
directly. This will be the focus of our future investigations.
However, our results focused on EPA are consistent with prior
literature implicating this PUFA in mood regulation and raises
interesting questions as to whether specific SNPs in the FADS
genes and other lipid metabolism control points may be useful in
guiding PUFA dietary or supplementation strategies that could
augment the treatment of bipolar patients through dietary
Materials and Methods
Bipolar disorder subjects, receiving an atypical antipsychotic
(olanzapine, quetiapine, risperidone or clozapine) were recruited
for this cross-sectional study, as reported previously . After
informed consent was obtained, subjects underwent metabolic
screening and fasted blood samples were drawn and used for
lipomic analysis. All recruitment, enrolling and data analysis were
done with the approval of the Institutional Review Board for
human subject use at the University of Michigan and written
consent for the studies was obtained from all subjects. Medical and
demographic data for the subjects are summarized in Table 2,
separated into suicide attempter and non attempter groups.
Total fasted plasma lipid profiles were obtained from 27 bipolar
subjects who were dual enrolled in a second study, for which
detailed psychiatric data were available. Total lipids were
extracted from the plasma according to the method of Bligh and
Dyer . Heptadecanoic acid internal standard for lipid sub-
classed was added to each sample prior to extraction. After
hydrolysis, lipids were methylated and analyzed on an Omega
Wax 250 capillary column (Supelco) using an Agilent 6890 gas
chromatograph. Relative abundance of 22 different naturally
occurring fatty acid and 3 trans-fatty acid species were done by
Table 2. Subject Data.
Age GenderCurrent AAP Dose (mg/day)CPZ eqs.BMI Suicide Hx
53F Quetiapine300170.9 25 No
64M NA NA0.0 32No
26F Aripiprazole5 62.722 No
56F Aripiprazole20250.9 45No
51F Quetiapine 400 227.933 No
45M Quetiapine600 341.938 No
61F Risperidone4 332.129No
22F Aripiprazole 7.594.122Yes
33F Paliperidone3 38 Yes
54M Aripiprazole 15188.2 33Yes
50MAripiprazole 25313.6 24Yes
25F Risperidone2 166.021 Yes
25F NANA 0.039Yes
42F NANA 0.020 Yes
42M Risperidone2 166.031Yes
38M Olanzapine7.5140.7 30Yes
56F Risperidone1 83.033Yes
56F NA NA0.0 29Yes
54F NANA 0.043 Yes
Atypical antipsychotic (AAP) medications are given with actual dose and chlorpromazine equivalents (CPZ eqs.). Body mass index (BMI) and history of suicide attempt
(Suicidal Hx), either Yes or No are also reported.
Lipids, Personality and Suicide Risk
PLoS ONE | www.plosone.org6January 2012 | Volume 7 | Issue 1 | e29297
comparison of retention times with known standards. FADS2 Download full-text
activity estimates were calculated using the ratio of 18:3 (n-6) to
The revised NEO personality inventory (NEO-PI-R) was used
to measure the five personality factor scores (neuroticism,
extraversion, openness, agreeableness and conscientiousness). We
chose to normalize the NEO-PI-R data to the S-Form and all
factors were calculated as per the NEO-PI-R manual . (NEO
PI-R professional manual. Odessa, FL: Psychological Assessment
Resources, Inc.). Suicidal history was extracted from a clinician
directed interview using the Diagnostic Interview for Genetic
Studies (DIGS, ). All subjects were also completed a Young
Mania Rating Scale and a Hamilton Depression Scale on the same
day as the NEO-PI. Twenty one subjects showed no signs of mania
(score,8), 4 showed a slight increase in mania (score 9–11), one
showed moderate mania (score=16) and one showed elevated
mania (score=33). Fifteen showed no depression (score,8), 8
showed minor depression (score 9–15), and 4 showed moderate
depression (score 16–20).
Data were analyzed with SPSS 19 software (IBM) using a
bivariate correlation analysis for the lipid concentration - person-
ality factor score correlations; and linear multivariate analysis for
group comparisons between suicide attempter and non-attempter
groups, using age, BMI and antipsychotic medication dose
(normalized to chlorpromazine equivalents by the method of
Andreasen, et al. ) as covariates in the model.
Conceived and designed the experiments: SJE. Performed the experiments:
SJE VLE CFB. Analyzed the data: SJE VLE CFB ARP MK. Contributed
reagents/materials/analysis tools: SJE ARP GJH MGM VLE MK CFB.
Wrote the paper: SJE.
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PLoS ONE | www.plosone.org7 January 2012 | Volume 7 | Issue 1 | e29297