Fatty acids in depressive and anxiety disorders Thesing, C.S.
2020
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Thesing, C. S. (2020). Fatty acids in depressive and anxiety disorders: Fishing for answers.
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Download date: 11. Oct. 2021
Chapter 3
The association of omega-3 fatty acid levels with personality
and cognitive reactivity
Carisha S. Thesing, Mariska Bot, Yuri Milaneschi,
Erik J. Giltay and Brenda W.J.H. Penninx
Published in Journal of Psychosomatic Research, 108 (2018), 93-101
Objective: Low omega (n)-3 polyunsaturated fatty acid (PUFA) levels have been found in patients with various major psychiatric disorders. This study aims to identify whether psychological vulnerabilities (personality and cognitive reactivity) underlying these psychiatric conditions are also associated with n-3 PUFA blood levels.
Methods: Data was used from 2912 subjects (mean age 41.9 years, 66.4% female) from the Netherlands Study of Depression and Anxiety (NESDA). Five personality dimensions (NEO Five Factor Inventory) and cognitive reactivity measures (Leiden Index of Depression Sensitivity-Revised and Anxiety Sensitivity Index) were assessed. Plasma n-3 PUFA and docosahexaenoic acid (DHA) levels (as ratios against total fatty acids; mmol%) were assessed using a nuclear magnetic resonance platform.
Results: Low n-3 PUFA and DHA levels were associated with high neuroticism (Standardized beta (Beta)=-.045, 95% Confidence Interval (CI)=-.079– -.010, p=.011; Beta=-.058, 95%CI=-.093 – -.022, p=.001), low extraversion (Beta=.065, 95%CI=.031–.099, p<.001; Beta=.074, 95%CI=.039–.109, p<.001) and low conscientiousness (Beta=.060, 95%CI=.027–.093, p<.001; Beta=.074, 95%CI=.039–
.108, p<.001). Low n-3 PUFA and DHA levels were related to high hopelessness/suicidality (Beta=- .059, 95%CI=-.096– -.023, p=.001; Beta=-.078, 95%CI=-.116– -.041, p<.001), but not with other cognitive reactivity measures. Directions of associations were generally consistent in subjects with and without a current depressive disorder.
Conclusion: Low n-3 PUFA and DHA levels are associated with personality (high neuroticism, low extraversion and low conscientiousness) and cognitive reactivity (high hopelessness/suicidality).
Effect sizes were rather small, but in line with previous research on personality and chronic diseases.
Future research should examine which lifestyle and/or biological pathways underlie these associations.
Introduction
Low omega-3 polyunsaturated fatty acid (n-3 PUFA) levels, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) blood levels (constituents of n-3 PUFA), have been associated with several major psychiatric disorders, for example mood disorders (unipolar and bipolar disorders), schizophrenia, attention deficit hyperactivity disorder (ADHD), impulse control disorders (including aggression), and a higher suicide risk (Freeman, 2000; Hallahan & Garland, 2004; Hibbeln & Salem, 1995; Peet & Stokes, 2005; Richardson & Puri, 2002; Skosnik & Yao, 2003; Thesing, Bot, Milaneschi, Giltay, & Penninx, 2018). Many psychiatric disorders have a heterogeneous etiology and are overlapping in symptoms (Goldberg, 1993; Lara & Akiskal, 2006; Matsuo et al., 2015; Zavos et al., 2016). Therefore, some research has shifted towards examining whether PUFA blood levels might be associated with more general dimensional constructs or endophenotypic traits underlying these disorders (Conklin, Harris, et al., 2007; Conklin, Manuck, et al., 2007; Evans et al., 2012; Mincke, Cosyns, Christophe, De Vriese, & Maes, 2006), further referred to as psychological vulnerabilities.
One of these psychological vulnerabilities may be personality traits, with its widely used dimensions of neuroticism, extraversion, openness, agreeableness and conscientiousness (Goldberg, 1993; John
& Srivastava, 1999; McCrae & Terracciano, 2005). In particularly high neuroticism, but also low extraversion and to a lesser extent low openness, agreeableness and conscientiousness have been associated with increased risk of psychiatric disorders such as depressive and anxiety disorders and substance abuse (Khan et al., 2005; Kotov, Gamez, Schmidt, & Watson, 2010; Krueger, 1999).
Interestingly, low levels of n-3 PUFAs have also shown to be significantly associated with high neuroticism (Conklin, Harris, et al., 2007; Conklin, Manuck, et al., 2007) and low extraversion (Evans et al., 2012), low openness (Evans et al., 2012), low agreeableness (Conklin, Harris, et al., 2007; Evans et al., 2012; Mincke et al., 2006), and low conscientiousness (Mincke et al., 2006), although one study found no significant associations (Tsuchimine, Kaneda, & Yasui-Furukori, 2016). However, the studies that do find significant associations had small sample sizes (ranging from 27 till 279) and some included only mentally healthy participants or a specific patient group (e.g. patients with bipolar disorder or paedophiles) (Evans et al., 2012; Mincke et al., 2006).
Cognitive reactivity is another psychological vulnerability that might be associated with PUFA blood levels. Cognitive reactivity has been described as the more specific, cognitive manifestation of personality traits (Barnhofer & Chittka, 2010; Drost et al., 2012; Muris, Roelofs, Rassin, Franken,
& Mayer, 2005; Roelofs, Huibers, Peeters, Arntz, & van Os, 2008) and is the ease at which negative thinking patterns are reactivated through minor triggers (Barnhofer & Chittka, 2010; Van der Does, 2002). It is usually divided into hopelessness/suicidality, acceptance/coping, aggression, control/
perfectionism, risk aversion/harm avoidance, rumination and anxiety sensitivity (Van der Does, 2002). Cognitive reactivity has been associated with the development, maintenance, and recurrence of depression (Abrams et al., 2004; Drost et al., 2012; Egan, Wade, & Shafran, 2011; Fresco, Frankel, Mennin, Turk, & Heimberg, 2002; Hong, 2007; Limburg, Watson, Hagger, & Egan, 2016; Mandelli et al., 2012; Muris et al., 2005; Roelofs et al., 2008; Shallcross, Troy, Boland, & Mauss, 2010; Smoski et al., 2014). Of these cognitive reactivity measures, only the associations between aggression and DHA and EPA have been studied, for which negative associations were found (Gajos & Beaver, 2016; Garland
& Hallahan, 2006; Hibbeln, Ferguson, & Blasbalg, 2006), for example in depressed patients (Beier et al., 2014).
Several mechanisms may be responsible for the association between n-3 PUFA and psychological
vulnerabilities. n-3 PUFAs are known to have a positive effect on brain functioning: the anti-
inflammatory property of n-3 PUFAs may mitigate an overactive immune system associated with
mood disorders (Young & Conquer, 2005). Furthermore, an increase in dietary DHA has been related
to an increase in cortical serotonin and dopamine, which have been implicated in the etiology of
several mental disorders (Smith, Beilin, & Mori, 2011; Young & Conquer, 2005). Fatty acids may play a role in neural membrane fluidity and receptor binding (Owen, Rees, & Parker, 2008; Smith et al., 2011; Stahl, Begg, Weisinger, & Sinclair, 2008) as, for instance, DHA can affect neurological function by modulating neurotransmission, neurogenesis, and myelination (Weiser, Butt, & Mohajeri, 2016).
Therefore, they may indirectly impact on cognitive functioning, which is associated with personality (Soubelet & Salthouse, 2011). Both low-grade inflammation, a neurotransmitter inbalance, and the resulting lower serotonin levels (Beier et al., 2014; Owen et al., 2008; Smith et al., 2011; Stahl et al., 2008; Weiser et al., 2016; Young & Conquer, 2005) have shown to be associated with cognitive reactivity (Booij & Van der Does, 2007; Firk & Markus, 2009; Gajos & Beaver, 2016; Meyer et al., 2003;
Wells, Beevers, & McGeary, 2010). However, n-3 PUFA levels could also be affected by personality and cognitive reactivity, as some personality traits and cognitive reactivity measures have been associated with dietary choices, including the frequency of fish intake, which is rich in n-3 PUFAs (Anestis, Holm-Denoma, Gordon, Schmidt, & Joiner, 2008; Anestis, Selby, Fink, & Joiner, 2007; Brown, Parman, Rudat, & Craighead, 2012; Cropley, Michalianou, Pravettoni, & Millward, 2012; Forman, Hoffman, Juarascio, Butryn, & Herbert, 2013; Igna, Julkunen, Lipsanen, & Vanhanen, 2013; Lunn, Nowson, Worsley, & Torres, 2014; Mõttus et al., 2012).
Taken together, there are only a few studies (of which most with a small sample size) that comprehensively investigated the relationship between n-3 PUFAs and one or more psychological vulnerabilities that may underlie several psychiatric disorders. The associations of n-3 PUFAs with some cognitive reactivity measures have not been studied at all. Most of the studies only included healthy individuals or patients with one specific psychiatric disorder and there has not been a study including all psychological vulnerabilities together in one study. Therefore, the aim of this large-scale cross-sectional study is to investigate the association all these psychological vulnerabilities with n-3 PUFAs and DHA in a large sample, including both currently healthy and currently psychiatrically ill participants. By including both currently healthy and psychiatrically ill individuals, a wide range of variation in psychological vulnerabilities was available.
Materials and Methods
Study sample
Between 2004 and 2007, 2981 participants aged between 18 and 65 years were recruited from the Dutch general population (19%), primary health care (54%) and specialized mental health care (27%) to participate in the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal observational cohort study (Penninx et al., 2008). The research protocol was approved by ethics committees of participating universities. All respondents provided written informed consent.
Exclusion criteria were a poor comprehension of the Dutch language and having a primary clinically overt diagnosis of another (e.g. psychotic, obsessive–compulsive, bipolar or severe addiction) disorder.
For this study, baseline data was used as that is when n-3 PUFA levels were assessed. Participants provided blood samples (after instructions for overnight fast) and underwent a psychiatric interview.
For this study, we excluded 69 participants (2.3%) due to missing blood samples, resulting in a sample size of 2912. The investigation was carried out in accordance with the latest version of the Declaration of Helsinki.
PUFA assessment
As described before (Thesing et al., 2018), the fatty acids measured are esterified fatty acids stemming
from the lipoprotein particles, so these are not free fatty acids in the plasma but rather bound within
cholesteryl esters, triglycerides and phospholipids inside lipoproteins particles. They were assessed
in EDTA plasma samples which were stored at -80°C for later assessment. Blood samples were
shipped in 2 batches (April and December 2014, further referred to as metabolic assessment wave 1
and 2, respectively). In 2015, among other metabolites, PUFA levels were quantified at 22°C using a commercially available high-throughput proton Nuclear Magnetic Resonance (NMR) metabolomics platform (Nightingale Health Ltd., Helsinki, Finland) (Soininen, Kangas, Würtz, Suna, & Ala-Korpela, 2015). Fatty acid metabolism is influenced by several factors, for example use of statins or estrogens (Giltay, 2004; Giltay, Gooren, Toorians, Katan, & Zock, 2004; Würtz et al., 2016). Therefore, relative PUFA measures (as percentage of total fatty acids yielding mmol% values) have been found biologically more informative, because this reflects PUFA levels in relation to overall fatty acid levels and better accounts for the interrelationship between these two (Willett, 1998). Spearman rho correlations (Supplementary table 1) show that absolute and relative measures are highly correlated. The present analyses focused primarily on relative measures. Additional results based on absolute values are presented in the supplemental materials.
Psychological vulnerabilities
Personality traits were determined by the NEO Five-Factor Inventory (NEO-FFI), a short form of the Revised NEO Personality Inventory (NEO-PI-R) (Costa & McCrae, 1995). The NEO-FFI is a self-report questionnaire consisting of 60 items with a five-point scale (0 through 4) assessing five personality domains (neuroticism, extraversion, openness, agreeableness, and conscientiousness) with a minimum score of 12 and a maximum total score of 60 per domain. Psychometric studies indicated good psychometric properties for the NEO-FFI, with high internal consistency, retest stability and cross-observer validity (McCrae, Kurtz, & Terracciano, 2011; Thalmayer, Saucier, & Eigenhuis, 2011).
Cognitive reactivity was assessed by the Leiden Index of Depression Sensitivity-Revised (LEIDS-R) (Van der Does, 2002) and the Anxiety Sensitivity Index (ASI) (Reiss, Peterson, Gursky, & McNally, 1986). The LEIDS-R is a self-report questionnaire consisting of 34 items with a five-point scale (0 through 4) assessing six subscales (hopelessness/suicidality, acceptance/coping, aggression, control/
perfectionism, risk aversion/harm avoidance and rumination) with a minimum total score of 0 and a maximum score of 136 (with higher scores indicating a more pronounced cognitive reaction to sad mood). The LEIDS-R has been found to discriminate between never-depressed and recovered depressed patients (Moulds et al., 2008; Van der Does, 2002). Longitudinal studies support the reliability and validity of the LEIDS-R (Antypa, Van der Does, & Penninx, 2010; Giesbrecht et al., 2009; Raes, Dewulf, Van Heeringen, & Williams, 2009; Williams, Van Der Does, Barnhofer, Crane,
& Segal, 2008). The ASI is a self-report questionnaire consisting of 16 items with a five-point scale (0 through 4) with higher scores indicating a more pronounced cognitive reaction to anxiety (Reiss et al., 1986). Studies have shown the ASI total score to be a reliable and valid instrument (Peterson &
Heilbronner, 1987; Reiss et al., 1986).
Covariates and effect modifiers
Sociodemographic covariates were age, gender, and education (years). Blood sampling covariates
were fasting status at time of blood withdrawal (yes/no), blood sample collection area (Amsterdam,
Leiden, or Groningen), and metabolic assessment wave (1/2). Lifestyle variables included were
current smoking status (never/current/former), use of alcohol (number of glasses per week), and
physical activity. Level of physical activity was measured using the total Metabolic Equivalent of Task
(MET) score derived from the International Physical Activity Questionnaire (IPAQ) and expressed
as MET-minutes per week (Craig et al., 2003). Somatic health variables were Body Mass Index (BMI,
continuous), diabetes (yes/no), heart disease (yes/no), number of other chronic somatic disorders
(continuous), use of lipid-modifying drugs (i.e. statins, yes/no), and use of n-3 PUFA supplements
(yes/no). Body Mass Index was calculated as the measured weight(kg)/length(m)
2. As we expected
that in particular diagnosis of diabetes and heart disease (cerebrovascular disease, coronary heart
disease, congestive heart failure, arrhythmia, or other) would be related to PUFAs (Würtz et al., 2015),
we separated these from other chronic somatic diseases in our models. Other self-reported somatic
diseases included thyroid disease, osteoarthritis, intestinal disorders, liver disease, cancer, neurological
conditions, and allergies. Use of lipid-modifying drugs (i.e. statins) and n-3 PUFA supplements were
derived from drug container inspection and were considered as these could affect PUFA blood levels (Würtz et al., 2016). Diagnoses of depressive (major depressive disorder or dysthymia) and anxiety disorders (social phobia, generalized anxiety disorder, panic disorder and agoraphobia) within the last month according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) were ascertained using the Composite International Diagnostic Interview (CIDI, versions 2.1) (Wittchen, 1994), administered by trained researchers.
Statistical analysis
The n-3 PUFA and DHA (mmol%) were transformed using the natural log due to their positively skewed distributions. In the total sample, (multivariable) linear regression analyses were performed to examine the association of n-3 PUFA and DHA (mmol%) as dependent variables with psychological vulnerabilities as independent variables. Model 1 was the unadjusted model. Model 2 was adjusted for age, gender, education, fasting status, blood sample collection area, metabolic assessment wave, smoking status, use of alcohol, physical activity, BMI, heart disease, diabetes, number of other chronic somatic disorders, use of lipid-modifying drugs and use of n-3 PUFA supplements. To correct for multiple testing, a False Discovery Rate (FDR) according to the Benjamini-Hochberg procedure was used based on 12 tests per PUFA measure per model reflecting the 12 psychological measures (Benjamini & Hochberg, 1995). As additional analysis we studied which personality and cognitive reactivity was most strongly and independently related to n-3 PUFA and DHA by putting the significant personality and cognitive reactivity measures together in one fully adjusted model (model 3). Analyses were repeated for the absolute values of n-3 PUFA and DHA (in mmol/l). To check whether there was a case of multicollinearity, variance inflation factors (VIF) were checked.
To explore the presence of a dose-response association of n-3 PUFA and DHA with the psychological vulnerabilities that showed a significant association with n-3 PUFA and DHA in the total sample, we plotted the fully adjusted mean scores of these vulnerabilities for different bins of n-3 PUFA and DHA levels. These figures were made in SigmaPlot (Systat Software, San Jose, CA).
The present sample contained a large proportion (n=833, 28.6%) of subjects with a current depressive disorder (e.g. within the past month). As our previous study showed that currently depressed patients – but not those with remitted depression or anxiety disorders - had significantly lower n-3 PUFA levels (Thesing et al., 2018), we examined whether the associations between psychological vulnerabilities and PUFAs were consistent across depressive disorder status (patients with a current depressive disorder versus all others with no current depressive disorder). In linear regression models, disorder-by- psychological vulnerability interaction terms were included together with the terms for the respective main effects. Analyses examining the association between PUFA and psychological vulnerabilities were repeated in a subsample of subjects without a current depressive disorder diagnosis.
To check whether there is a potential impact of n-3 PUFA supplement use and statin use on the association of plasma PUFA levels and psychological vulnerabilities, a sensitivity analysis was performed including only participants without n-3 PUFA supplement or statin use. All analyses were conducted using IBM SPSS statistics software, version 22 (IBM Corp., Armonk, NY, USA).
Results
Sample characteristics
Table 1 shows the demographic characteristics of the total sample (N=2912). Participants had a mean
age of 41.9 (Standard Deviation (SD)=13.0) and 66.4% were female. Of all participants, 95.4% were
fasting at time of blood withdrawal. The fasting participants showed no significant differences in
PUFA blood levels compared to the 4.6% non-fasting participants. The median n-3 PUFA and DHA
levels (mmol%) were 3.17 (Interquartile range (IQR)=0.94) and 1.18 (IQR=0.49), respectively. The Pearson coefficients of correlations between psychological vulnerabilities (Supplementary Table 2) ranged from 0.004 to 0.768.
Psychological vulnerabilities and PUFAs in the total sample
Table 2 shows that after full adjustment (model 2), lower n-3 PUFAs levels were significantly associated with higher neuroticism (Beta=-.045, 95% Confidence Interval (CI)=-.079 – -.010, p=.011) and hopelessness/suicidality (Beta=-.059, 95%CI=-.096 – -.023, p=.001), and with lower extraversion (Beta=.065, 95%CI=.031–.099, p<.001) and conscientiousness (Beta=.060, 95%CI=.027–.093, p<.001).
After full adjustment, lower DHA was significantly associated with higher neuroticism (Beta=-
Table 1. Characteristics of the study sample.
Total (n=2912) Sociodemographic variables
Age in years, mean (SD) 41.9 (13.0)
Female% 66.4
Years of education, mean (SD) 12.2 (3.3)
Blood sampling variables
Fasting at time of blood withdrawal% 95.4
Blood sample collection area
Amsterdam% 40.8
Leiden% 30.5
Groningen% 28.7
First metabolic assessment wave% 54.5
Lifestyle and somatic health Smoking status
Current% 38.7
Former% 33.6
Never% 27.8
Number of glasses of alcohol per week, median (IQR) 3.7 (8.5)
Total MET-minutes per week, median (IQR) 3075 (3411)
BMI, median (IQR) 24.7 (6.03)
Number of chronic somatic diseases, median (IQR) 1.0 (1.0)
Diabetes Mellitus% 4.0
Heart disease% 8.4
Use of statins% 6.8
Use of n-3 PUFA supplements, yes% 4.0
PUFAs
n-3 PUFA (mmol%), median (IQR) 3.17 (0.94)
DHA (mmol%), median (IQR) 1.18 (0.49)
Personality
Neuroticism, mean (SD) 37 (9)
Extraversion, mean (SD) 37 (7)
Openness, mean (SD) 38 (6)
Agreeableness, mean (SD) 44 (5)
Conscientiousness, mean (SD) 42 (6)
Cognitive vulnerability to depression
Hopelessness/suicidality, median (IQR) 3 (6)
Acceptance/coping, median (IQR) 1 (2)
Aggression, median (IQR) 4 (5)
Control/perfectionism, median (IQR) 5 (6)
Risk aversion/harm avoidance, median (IQR) 8 (7)
Rumination, median (IQR) 9 (8)
Cognitive vulnerability to anxiety, median (IQR) 27 (12)
Psychiatric diagnosis
Current depressive or anxiety disorder,% 47.0
Currently healthy participants,% 53.0
Note. SD: Standard deviation. IQR: Interquartile Range. MET: Metabolic Equivalent of Task. BMI: Body Mass Index. DHA:
docosahexaenoic acid. n-3 PUFA: omega-3 polyunsaturated fatty acids. N.A.: Not Applicable.
Table 2. Association between personality traits and cognitive vulnerability as determinants and n-3 PUFA and n-3 PUFA (mmol%)
Model 1 Model 2 Model 3
Beta p-value Beta p-value Beta p-value
Personality
Neuroticism -.130 <.001* -.045 .011* .026 .35
Extraversion .070 <.001* .065 <.001* .044 .074
Openness .078 .001* .019 .28
Agreeableness .059 .002* -.013 .44
Conscientiousness .120 <.001* .060 <.001* .051 .018*
Cognitive vulnerability
Hopelessness/suicidality -.128 <.001* -.059 .001* -.037 .115
Acceptance/coping -.009 .66 -.011 .53
Aggression -.105 <.001* -.017 .35
Control/perfectionism -.046 .020 -.019 .30
Risk aversion/harm avoidance -.066 .001* -.018 .33
Rumination -.074 <.001* -.030 .105
Anxiety sensitivity -.034 .087 -.002 .90
Note. Model 1: unadjusted linear regression analyses for all predictor variables separately. Model 2: same as model 1 and significant predictor variables in the same model. n-3 PUFA (mmol%): percentage of n-3 PUFA of total Fatty Acids. DHA testing using the False Discovery Rate Benjamini-Hochberg procedure based on 12 tests per PUFA measure per model.
.058, 95%CI=-.093 – -.022, p=.001) and hopelessness/suicidality (Beta=-.078, 95%CI=-.116 – -.041, p<.001), and with lower extraversion (Beta=.074, 95%CI=.039–.109, p<.001) and conscientiousness (Beta=.073, 95%CI=.039–.108, p<.001). All of the abovementioned results remained significant after correction for multiple testing. Table 3 in the supplement shows that findings for absolute measures of n-3 PUFA and DHA (mmol/l) were consistent with the relative measures (mmol%) reported above.
Figure 1 shows the dose-response association of n-3 PUFA and DHA with neuroticism, extraversion, conscientiousness and hopelessness/suicidality in the total sample. The fully adjusted mean scores of these vulnerabilities were plotted for different n-3 PUFA and DHA levels and indicated a general pattern of linear associations.
To study whether these dimensions were related to n-3 PUFA and DHA outcomes independently from each other we included all significant psychological vulnerabilities of model 2 in one fully adjusted model (model 3 of Table 2). Low conscientiousness was the only significant predictor of n-3 PUFA (Beta=.051, 95%CI=.009–.094, p=.018) and DHA (Beta=.065, 95%CI=.023–.111, p=.003). Variance Inflation Factors show that multicollinearity was not present (all <10).
Sensitivity analysis
We examined whether the associations between PUFA and psychological vulnerabilities were consistent across current depressive disorder status. None of the 24 tested interaction terms between psychological vulnerabilities and depressive disorder status were significant after adjustment for multiple testing. Directions of associations were overall consistent in subjects with versus those without current depression, suggestive that the relationship between PUFA and psychological vulnerabilities was not modified by depressive disorder status. Supplementary table 4 shows the results obtained in the subsample of only currently non-depressed participants (n=2079), confirming that the positive relationships of extraversion (with DHA) and conscientiousness (with both n-3 PUFA and DHA) were also present in currently non-depressed participants.
There were no significant differences in psychological vulnerabilities between n-3 PUFA supplement
or statin users (n=309, 10.6%) and non-users, however as expected significantly higher n-3 PUFA and
DHA were found in n-3 PUFA supplement users and statin users (Median=3.79, IQR=1.16;
Table 2. Association between personality traits and cognitive vulnerability as determinants and n-3 PUFA and n-3 PUFA (mmol%)
Model 1 Model 2 Model 3
Beta p-value Beta p-value Beta p-value
Personality
Neuroticism -.130 <.001* -.045 .011* .026 .35
Extraversion .070 <.001* .065 <.001* .044 .074
Openness .078 .001* .019 .28
Agreeableness .059 .002* -.013 .44
Conscientiousness .120 <.001* .060 <.001* .051 .018*
Cognitive vulnerability
Hopelessness/suicidality -.128 <.001* -.059 .001* -.037 .115
Acceptance/coping -.009 .66 -.011 .53
Aggression -.105 <.001* -.017 .35
Control/perfectionism -.046 .020 -.019 .30
Risk aversion/harm avoidance -.066 .001* -.018 .33
Rumination -.074 <.001* -.030 .105
Anxiety sensitivity -.034 .087 -.002 .90
Note. Model 1: unadjusted linear regression analyses for all predictor variables separately. Model 2: same as model 1 and significant predictor variables in the same model. n-3 PUFA (mmol%): percentage of n-3 PUFA of total Fatty Acids. DHA testing using the False Discovery Rate Benjamini-Hochberg procedure based on 12 tests per PUFA measure per model.
.058, 95%CI=-.093 – -.022, p=.001) and hopelessness/suicidality (Beta=-.078, 95%CI=-.116 – -.041, p<.001), and with lower extraversion (Beta=.074, 95%CI=.039–.109, p<.001) and conscientiousness (Beta=.073, 95%CI=.039–.108, p<.001). All of the abovementioned results remained significant after correction for multiple testing. Table 3 in the supplement shows that findings for absolute measures of n-3 PUFA and DHA (mmol/l) were consistent with the relative measures (mmol%) reported above.
Figure 1 shows the dose-response association of n-3 PUFA and DHA with neuroticism, extraversion, conscientiousness and hopelessness/suicidality in the total sample. The fully adjusted mean scores of these vulnerabilities were plotted for different n-3 PUFA and DHA levels and indicated a general pattern of linear associations.
To study whether these dimensions were related to n-3 PUFA and DHA outcomes independently from each other we included all significant psychological vulnerabilities of model 2 in one fully adjusted model (model 3 of Table 2). Low conscientiousness was the only significant predictor of n-3 PUFA (Beta=.051, 95%CI=.009–.094, p=.018) and DHA (Beta=.065, 95%CI=.023–.111, p=.003). Variance Inflation Factors show that multicollinearity was not present (all <10).
Sensitivity analysis
We examined whether the associations between PUFA and psychological vulnerabilities were consistent across current depressive disorder status. None of the 24 tested interaction terms between psychological vulnerabilities and depressive disorder status were significant after adjustment for multiple testing. Directions of associations were overall consistent in subjects with versus those without current depression, suggestive that the relationship between PUFA and psychological vulnerabilities was not modified by depressive disorder status. Supplementary table 4 shows the results obtained in the subsample of only currently non-depressed participants (n=2079), confirming that the positive relationships of extraversion (with DHA) and conscientiousness (with both n-3 PUFA and DHA) were also present in currently non-depressed participants.
There were no significant differences in psychological vulnerabilities between n-3 PUFA supplement or statin users (n=309, 10.6%) and non-users, however as expected significantly higher n-3 PUFA and DHA were found in n-3 PUFA supplement users and statin users (Median=3.79, IQR=1.16;
DHA (mmol%) as outcome variables in the total sample (n=2912).
DHA (mmol%)
Model 1 Model 2 Model 3
Beta p-value Beta p-value Beta p-value
-.109 <.001* -.058 .001* .011 .69
.094 <.001* .074 <.001* .036 .15
.074 <.001* -.013 .48
.064 .001* -.023 .20
.114 <.001* .073 <.001* .065 .003*
-.128 <.001* -.078 <.001* -.046 .056
-.001 .958 .009 .63
-.090 <.001* -.016 .41
-.031 .123 -.017 .37
-.065 .001* -.028 .13
-.066 .001* -.036 .058
-.028 .162 -.004 .84
adjusted for socio-demographic, sampling, lifestyle and somatic health variables. Model 3: same as model 2 but with all (mmol%): percentage of DHA of total Fatty Acids. Beta: standardized beta’s. *Significant after correction for multiple
Median=1.36, IQR=0.47, respectively) compared to non-users (Median=3.27, IQR=0.90; Median=1.17, IQR=0.48, respectively), p<.001 and p<.001. Supplementary table 5 shows that associations between n-3 PUFA and DHA and neuroticism, extraversion, conscientiousness and hopelessness/suicidality were comparable after removing the n-3 PUFA supplement users and statin users from the sample.
Conclusions
Using data from a large cohort, we examined the association of n-3 PUFA blood concentrations with psychological vulnerabilities commonly associated with increased risk of psychopathology. The present findings showed that lower n-3 PUFA and DHA levels were associated with high levels of neuroticism and hopelessness/suicidality, and with lower levels of extraversion and conscientiousness.
Associations were overall consistent in subjects with versus without current depression and also significantly present in currently non-depressed participants.
We found significant negative associations of n-3 PUFA and DHA levels with neuroticism, which is in line with most previous research (Conklin, Harris, et al., 2007; Conklin, Manuck, et al., 2007), although not with one study that found no significant association between neuroticism and n-3 PUFA levels (Tsuchimine et al., 2016). One explanation for this finding is dietary habits. Next to DHA and EPA, n-3 PUFAs consist of other constituents, i.e. α-linolenic acid (ALA), which are so-called essential fatty acids as humans must ingest them through the diet (e.g. EPA and DHA from fatty fish and ALA from green vegetables, nuts, and seeds), or through supplements as their body requires them for good health but can hardly synthesize them (Young & Conquer, 2005). Experts have not established normal ranges, but mean levels for plasma phospholipid EPA plus DHA among U.S. adults not taking n-3 PUFA supplements are about 3%–4% (Brasky et al., 2013, 2011; Harris et al., 2004). Plasma fatty acid levels, however, can vary substantially based on an individual’s most recent meals, so they do not reflect long-term dietary consumption (Thiebaut et al., 2009). This makes diet the most important contributor to n-3 PUFA plasma levels (Andersen et al., 1999; Ma, Folsom, Shahar, & Eckfeldt, 1995).
Therefore, the association between high neuroticism and low n-3 PUFA plasma levels may be due to
unhealthy food choices (Lunn et al., 2014; Mõttus et al., 2013, 2012), resulting in low n-3 PUFA intake
and low n-3 PUFA blood levels. This may be via the association of high neuroticism with certain
dysfunctional eating styles, such as emotional eating and external eating (Keller & Siegrist, 2015), which have shown to negatively influence food choices (van Strien, Herman, & Verheijden, 2009; Van Strien & Van de Laar, 2008). Additionally to the pathway via dietary habits, high neuroticism has also been associated with high basal cortisol levels (Laceulle, Nederhof, van Aken, & Ormel, 2015), high inflammation (Sutin et al., 2010) and low heart rate variability (Dermody et al., 2016), which have all been associated with low n-3 PUFA blood levels (Christensen, 2011; Eide et al., 2016; Ferrucci et al., 2006; Larrieu et al., 2014; Mocking et al., 2013; Yates, Calder, & Ed Rainger, 2014).
We found significantly positive associations of n-3 PUFA with extraversion and conscientiousness.
The strongest association with n-3 PUFA and DHA was found for low conscientiousness, and this personality trait was independently of the other significant traits related to lower n-3 PUFA and DHA. The associations of n-3 PUFA and DHA with extraversion and conscientiousness are in line with most previous research (Evans et al., 2012; Mincke et al., 2006), although not with one study conducted in a Japanese sample that found no significant association between extraversion and conscientiousness and PUFAs (Tsuchimine et al., 2016). This could express cultural differences in correlates of personality and the same has e.g. been found for conscientiousness and obesity, which was present in most European-descent samples but not in the few Asian samples that investigated this (Sutin et al., 2015). Interestingly, previous studies have shown that high extraversion is associated with external eating (Keller & Siegrist, 2015), which has shown to be associated with more unhealthy food choices (van Strien et al., 2009; Van Strien & Van de Laar, 2008). The higher sociability of extraverted people, which is basically a health beneficial psychological resource, seems to have health-averse effects in this case (Keller & Siegrist, 2015). However, this is not in line with our study, in which we found that low extraversion was associated with low n-3 PUFA levels. High conscientiousness on the other hand, has been associated with a more restraint eating style and with less emotional eating and external eating (Keller & Siegrist, 2015), which have led to more healthy food choices (van Strien et al., 2009; Van Strien & Van de Laar, 2008). This way, high conscientiousness can lead to eating more products high in n-3 PUFA and consequently higher n-3 PUFA blood levels. Low extraversion and conscientiousness have also been associated with high basal cortisol levels (Laceulle et al., 2015) and additionally low conscientiousness has been associated with high inflammation (Luchetti, Barkley, Stephan, Terracciano, & Sutin, 2014; Sutin et al., 2010) and low heart rate variability (Dermody et al., 2016). Another underlying mechanism for the association of low conscientiousness and low n-3 PUFA and DHA levels may be that DHA has a beneficial impact on neural functioning (Beier et al., 2014; Owen et al., 2008; Smith et al., 2011; Stahl et al., 2008; Weiser et al., 2016; Young & Conquer, 2005), which may consequently have a positive influence on cognitive functioning. For example, a decrease in dietary DHA is related to a decrease in cortical serotonin and dopamine (Young &
Conquer, 2005) and both DHA and EPA are thought to play a role in neural membrane fluidity, ion channel functioning, and receptor binding (Owen et al., 2008; Smith et al., 2011; Stahl et al., 2008).
More specifically, DHA modulates neurotransmission, neurogenesis, myelination, inflammation and more (Oh et al., 2010; Weiser et al., 2016). According to a recent review cognitive functioning has been significantly associated with personality dimensions, for example conscientiousness, in some studies, while not in others (Meltzer et al., 2016).
In the present study, only for the personality dimensions neuroticism, extraversion and conscientiousness a significant association with n-3 PUFA and DHA was found, while not for the other personality dimensions. A personality profile with high neuroticism in combination with low extraversion and/
or low conscientiousness has previously shown to have an impact on several indicators of health,
including muscle strength (Tolea, Terracciano, Milaneschi, Metter, & Ferrucci, 2012), healthy sleep
(Duggan, Friedman, McDevitt, & Mednick, 2014), inflammation marker interleukin-6 (Sutin et al.,
2010) and BMI (Sutin, Ferrucci, Zonderman, & Terracciano, 2011) but also high conscientiousness on
its own has been associated with better health and longevity (Bogg & Roberts, 2013).
We found significant negative associations of n-3 PUFA and DHA with hopelessness/suicidality. No previous studies have examined this association before. N-3 PUFAs might be associated with cognitive reactivity due to their positive effect on brain functioning (Beier et al., 2014; Owen et al., 2008; Smith et al., 2011; Stahl et al., 2008; Weiser et al., 2016; Young & Conquer, 2005) and higher serotonin levels (Young & Conquer, 2005), which have been associated with less cognitive reactivity and less suicidal thoughts (Booij & Van der Does, 2007; Firk & Markus, 2009; Wells et al., 2010). Cognitive reactivity, such as rumination and anxiety sensitivity, has also been associated with emotional eating and external eating (Gibson, 2012; Hearon, Quatromoni, Mascoop, & Otto, 2014; Kubiak, Vögele, Siering, Schiel,
& Weber, 2008).
We found no association of n-3 PUFA and DHA with openness, agreeableness, acceptance/coping, aggression, control/perfectionism, risk aversion, rumination or anxiety sensitivity, which may mean that these vulnerabilities are not associated with n-3 PUFA according to the underlying mechanisms described above. This is not in line with the association between various psychological vulnerabilities and healthy food choices found in previous studies (Anestis et al., 2008, 2007; Brown et al., 2012;
Forman et al., 2013). An explanation may be that results of these studies and our study may be less comparable as these studies focused on healthy food choices in general, whereas the plasma n-3 PUFA measures can be seen as a more specific measure of higher n-3 PUFA intake. Additionally, as compared to previous studies, we adjusted our analyses for a wider range of covariates in order to substantially reduce the potential impact of residual confounding. Nevertheless, adjustment for a large set of covariates, in the case in which some of them may act as mediators, may potentially explain part of the estimated associations. The non-significant association of aggression with n-3 PUFAs is not in line with several studies that found associations between n-3 PUFA levels and aggression (Beier et al., 2014; Gajos & Beaver, 2016; Garland & Hallahan, 2006; Hibbeln et al., 2006). An explanation may be that in our study aggression is measured with a few self-report items, while in previous research more extensive measures of aggression (e.g. multi-item questionnaires or measures of physical aggression) were used.
Our findings suggest that the associations of n-3 PUFAs and DHA with the personality factors extraversion and, in particular, with conscientiousness, are consistent in both patients with a current depressive disorder and in persons without a current depressive disorder. This suggests that extraversion and conscientiousness may represent a third underlying factor with a major role in the development of the bidirectional link between depression and low n-3 PUFAs and low DHA. No association of n-3 PUFAs or DHA with hopelessness/suicidality was found in persons who were currently not depressed, which is as expected because hopelessness/suicidality is a construct that is inherently associated with depression. Our findings also suggest that the associations of n-3 PUFAs with psychological vulnerabilities are not dependent on current n-3 PUFA supplement or statin use.
Taken together, lower plasma levels of n-3 PUFA and DHA were in general associated with higher neuroticism and hopelessness/suicidality and with lower extraversion and conscientiousness.
The underlying mechanism(s) between PUFA blood levels and psychological vulnerabilities remain unknown and therefore more research is needed. Interestingly, neuroticism, extraversion, conscientiousness, hopelessness are all also linked to a diagnosis of depression, and less strongly with anxiety (Drost et al., 2012; Fresco et al., 2002; Hong, 2007; Khan et al., 2005; Kotov et al., 2010; Krueger, 1999; Muris et al., 2005; Roelofs et al., 2008) and therefore in line with our earlier findings for lower PUFA levels in depressed patients but not in anxious patients (Thesing et al., 2018).
This study has some limitations. First, only cross-sectional data was used so no conclusion on the direction of the association between PUFA levels, personality and cognitive reactivity can be drawn.
Overall, effect sizes for personality and cognitive reactivity were rather small and, therefore, their
clinical relevance has to be established. Nevertheless, they are comparable to effect sizes for personality
in previous research on for example illness burden and cholesterol (Sutin, Zonderman, Ferrucci, &
Terracciano, 2013; Sutin et al., 2010). The resolution of high throughput NMR does currently not allow sufficient resolution for robust, independent quantification of EPA due to spectral overlap, while EPA has often been found to be more effective than DHA in prior supplementation studies for depression (Mocking et al., 2016). NMR has a somewhat lower sensitivity compared to routine clinical chemistry (Würtz et al., 2017). However, it has shown to be a reliable quantification of a large panel of low-molecular–weight metabolites and lipid molecules, including fatty acids, in large-scale studies (Würtz et al., 2017). Regarding the effects of long-term storage, n-3 PUFA and DHA have shown to be relatively stable when stored at -75 °C (Metherel, Aristizabal Henao, & Stark, 2013). Dietary intake of n-3 PUFAs was not assessed, precluding the possibility to adjust for the effects of diet. Besides patients with depressive or anxiety disorders, no patients with other psychiatric disorders were included, which makes our results less generalizable to other psychiatric disorders. Important strengths of the present study are the large sample size, and the assessment of personality and cognitive reactivity with well-validated scales, and large number of plasma PUFA measures. One may suggest that it would be better to include in the main analyses only participants without a current disorder. However, by including both currently depressed or anxious patients and currently healthy participants in this study the statistical power was high and there was data available on the whole dimension of personality and cognitive reactivity.
In summary, lower blood levels of n-3 PUFA and DHA were associated with higher neuroticism and
hopelessness/suicidality and with lower extraversion and conscientiousness, and these associations
were not modified by current depression status. As both personality and cognitive reactivity are also
associated with depression (among other psychiatric disorders), this is in line with the findings of our
previous study on the association of n-3 PUFAs and DHA with depression diagnosis. Modulating
neuroticism, extraversion, conscientiousness and hopelessness/suicidality in patients may break the
link between low n-3 PUFA levels and depression. Future (longitudinal) research is needed to examine
these associations in other psychiatric disorders, to examine the possible causal pathways and to gain
more insight into the possible underlying mechanisms.
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