Omega-3 and omega-6 fatty acid levels in depressive and anxiety disorders
Introduction
The impact of polyunsaturated fatty acids (PUFAs) on health are well described. Omega-3 (N-3) PUFAs consist of e.g. α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and can be mainly found in fatty fish, some other seafood, and some nuts and seeds (James et al., 2000, Simopoulos, 1999). Some randomized controlled trials have shown that intake of N-3 PUFAs ameliorate or even prevent physical illnesses such as inflammatory (Giudetti and Cagnazzo, 2012, Simopoulos, 2002) and cardiovascular diseases (La Rovere and Christensen, 2015, Simopoulos, 1999), while others have not (Hoogeveen et al., 2014, Kromhout et al., 2010). Omega-6 (N-6) PUFAs consist of e.g. linoleic and arachidonic acid which are for example found in plant and vegetable seeds and oils, as found in margarines and many processed foods (James et al., 2000, Simopoulos, 1999). High N-6 PUFA intake has been associated with chronic inflammatory diseases, cardiovascular diseases, obesity, rheumatoid arthritis, and Alzheimer’s disease (Patterson et al., 2012). Low levels of N-3 and high levels of N-6 PUFAs have also been associated with neuropsychiatric disorders like depression and anxiety (Hibbeln and Salem, 1995).
Several potential biochemical mechanisms could explain the association between PUFAs and depression (Smith et al., 2011). The anti-inflammatory property of N-3 PUFAs may mitigate the overactive immune system associated with depression (Young and Conquer, 2005). Furthermore, a decrease in dietary DHA was related to a decrease in cortical serotonin and dopamine (Young and Conquer, 2005), and these neurotransmitters have been implicated in the etiology of depression (Smith et al., 2011, Young and Conquer, 2005). Fatty acids are implicated as regulators of gene transcription within the central nervous system (Alessandri et al., 2004, Smith et al., 2011) and may play a role in neural membrane fluidity and receptor binding (Owen et al., 2008, Smith et al., 2011, Stahl et al., 2008). For instance, DHA can affect neurological function by modulating neurotransmission, neurogenesis, myelination and more (Weiser et al., 2016).
Reviews and meta-analyses of observational studies have shown significantly lower N-3 PUFA blood levels in depressed individuals as compared to non-depressed individuals (Lin et al., 2010, Smith et al., 2011, Wani et al., 2015). However, most meta-analyses and reviews had small sample sizes (ranging from 10 to 118 depressed patients in individual studies (Lin et al., 2010)) and depression assessments between studies were diverse, from self-report questionnaires and clinical interviews to antidepressant prescriptions (Smith et al., 2011). There have been some small-scaled observational studies that found that higher n-3 PUFA blood levels were associated with lower depression severity (Adams et al., 1996, Edwards, 1998, Liu et al., 2013), especially those taking antidepressants (Féart et al., 2008), while no association with duration of depression has been found (Peet et al., 1998). Less is known about the role of clinical characteristics such as age of onset and recency of symptoms as these have never been studied in observational studies. Examining the difference in N-3 PUFA levels between current and remitted patients may help to clarify whether the association with for example N-3 PUFA is “state”-dependent (only present during an active episode and reversible after remission), or whether N-3 PUFA alterations may represent a constant underlying “trait” of depression. Although the relationship between N-6 PUFAs and depression have received much less attention, some found higher levels related to higher severity of depressive symptoms (Smith et al., 2011).
Since comorbidity of anxiety in depressive disorders is high, an association between anxiety and PUFAs is expected (Ross, 2009), however, much less examined. A recent study showed that participants with depression and comorbid anxiety had even lower N-3 PUFAs levels than depressed patients without comorbid anxiety(Liu et al., 2013). Lower N-3 PUFA levels have been found in social phobia (Green et al., 2006), but studies on other anxiety disorders are lacking. Others detected a linear relationship between N-3 PUFA intake and anxiety, with lower DHA intake being associated with a higher likelihood of anxiety (Jacka et al., 2012). This may indicate the possibility of additional anxiogenic impact of N-3 PUFAs deficiency.
Although numerous intervention studies with large sample sizes show that N-3 PUFA supplementation may have beneficial effects on depression (Appleton et al., 2015, Bloch and Hannestad, 2012, Grosso et al., 2014), large heterogeneity has been found in effect sizes. Some meta-analytic evidence (Appleton et al., 2010, Bloch and Hannestad, 2012), suggests a potential role of clinical depression characteristics in the efficacy of N-3 PUFA supplementation. Studies including more severe patients tend to show higher efficacy. However, others that not found this have suggested a role of depression subtypes, although they did not further speculate on which subtypes (Grosso et al., 2014).
To address the abovementioned issues, our primary aim is to examine the cross-sectional association of our primary outcomes N-3 and N-6 PUFA levels (both in absolute values and their ratio’s with total fatty acids), and our secondary outcomes DHA (both absolute and its ratio) and the N-6:N-3 PUFA ratio with remitted or current depressive and anxiety disorders, allowing us to be one of the first to examine whether there is a “trait”- or “state”-dependency of PUFA alterations and whether this is present in both disorders. It is hypothesized that N-3 measures (e.g. N-3 PUFA, N-3:FA ratio, DHA and DHA:FA ratio) will be lowest and N-6 PUFA measures (e.g. N-6 PUFA and N-6:FA) and the N-6:N-3 PUFA ratio will be highest going from persons with current depressive/anxiety disorders, to those with remitted depressive/anxiety disorders to healthy controls. In addition, our second aim is to explore whether specific clinical characteristics that often influence treatment response (severity, subtype, age of onset, duration and antidepressant use) can further differentiate patients with the largest PUFA differences, both for understanding the underlying mechanisms that link PUFA levels and psychiatric conditions, as well as for targeting the most appropriate patient group for future supplementation studies. It is hypothesized that those characteristics that indicate a worse disease course (higher severity, earlier age of onset, longer duration, use of antidepressants) are associated with unfavorable PUFA levels (lower N-3 PUFA levels and N-3:FA ratios and higher N-6 PUFA levels and N-6:FA ratios)(Driscoll et al., 2005, Henkel et al., 2006, Katon et al., 2010). We believe that our study has incremental value as to our knowledge this is one of the largest observational studies to date linking the presence and clinical characteristics of depressive as well as anxiety disorders to blood levels of PUFAs.
Section snippets
Study sample
Participants were selected from the Netherlands Study of Depression and Anxiety (NESDA), a longitudinal observational cohort study (Penninx et al., 2008). Between 2004 and 2007 in total 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%). The research protocol was approved by ethics committees of participating universities. All respondents provided written informed consent.
Sample characteristics
The included 2912 participants had a mean age of 41.9 years (SD = 13.04, range 18–65) and 1935 (66.4%) participants were female (Table 1). In the total sample the median DHA level was 0.13 mmol/l (Interquartile Range (IQR)=0.07), the median N-3 PUFA level was 0.36 mmol/l (IQR = 0.15) and the mean N-6 PUFA level was 3.94 mmol/l (SD = 0.75). The mean N-6:N-3 PUFA ratio was 10.94 (SD = 2.70). The median DHA:FA ratio was 1.13% (IQR = 0.49), the median N-3:FA ratio was 3.17% (IQR = 0.94) and the
Discussion
We examined the relationship of circulating N-3 and N-6 PUFA levels with current and remitted depressive and anxiety disorders and several of their clinical characteristics. Results showed that lower N-3 PUFA levels are only observed in patients with a current depressive disorder, especially in the more severe group with comorbid anxiety. Furthermore, lower N-3 PUFA levels were associated in a dose-response fashion with higher depressive symptoms severity. Finally, within patients with current
Conclusions
In summary, it can be concluded that currently depressed patients (especially the more severe cases with comorbid anxiety), but not those with remitted disorder or a current pure anxiety disorder, have lower circulating N-3 PUFA levels than healthy controls. The results implicate that clinicians, practitioners and researchers should be aware that currently depressed patients (especially those with more severe symptomatology) may be at high risk for low N-3 PUFA levels. Further studies are
Conflict of interest
None of the authors have any conflicts of interest.
Acknowledgments
The assessment of fatty acids was financially supported in part by BBMRI-NL, a Research Infrastructure financed by the Dutch government (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) [number 184033111].
The infrastructure for the NESDA study (www.nesda.nl) has been funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (Zon-Mw) [grant number 10-000-1002] and participating universities (VU University Medical Center, Leiden University
References (56)
- et al.
Updated systematic review and meta-analysis of the effects of n- 3 long-chain polyunsaturated fatty acids on depressed mood
Am. J. Clin. Nutr.
(2010) Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients
J. Affect. Disord.
(1998)- et al.
Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City Study
Am. J. Clin. Nutr.
(2008) - et al.
Beneficial effects of n-3 PUFA on chronic airway inflammatory diseases
Prostaglandins Other Lipid Mediat.
(2012) - et al.
Red cell membrane omega-3 fatty acids are decreased in nondepressed patients with social anxiety disorder
Eur. Neuropsychopharmacol.
(2006) - et al.
Disability in anxiety disorders
J. Affect. Disord.
(2014) - et al.
Treatment of depression with atypical features: a meta-analytic approach
Psychiatry Res.
(2006) - et al.
Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy
Am. J. Clin. Nutr.
(1995) - et al.
Dietary polyunsaturated fatty acids and inflammatory mediator production
Am. J. Clin. Nutr.
(2000) - et al.
The autonomic nervous system and cardiovascular disease: role of n-3 PUFAs
Vascul. Pharmacol.
(2015)
A meta-Analytic review of polyunsaturated fatty acid compositions in patients with depression
Biol. Psychiatry
Perspectives on alcohol consumption: liver polyunsaturated fatty acids and essential fatty acid metabolism
Alcohol
Omega-3 polyunsaturated fatty acids and anxiety disorders
Prostaglandins Leukot. Essent. Fat. Acids
The importance of the ratio of omega-6/omega-3 essential fatty acids
Biomed. Pharmacother.
Metabolomic profiling of statin use and genetic inhibition of HMG-CoA reductase
J. Am. Coll. Cardiol.
Omega-3 fatty acids and the treatment of depression: a review of scientific evidence
Integr. Med. Res.
Dietary fish intake and plasma phospholipid n-3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort
Am. J. Clin. Nutr.
Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression
Lipids
Polyunsaturated fatty acids in the central nervous system: evolution of concepts and nutritional implications throughout life
Reprod. Nutr. Dev.
Omega-3 fatty acids for depression in adults
Cochrane database Syst. Rev.
An inventory for measuring clinical anxiety: psychometric properties
J. Consult. Clin. Psychol.
Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis
Mol. Psychiatry
International physical activity questionnaire (IPAQ): 12-country reliability and validity
Med. Sci. Sport. Exerc.
Late-onset major depression: clinical and treatment-response variability
Int. J. Geriatr. Psychiatry
Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials
PLoS One
No effect of n-3 fatty acids supplementation on NT-proBNP after myocardial infarction: the Alpha Omega Trial
Eur. J. Prev. Cardiol.
Dietary intake of fish and PUFA, and clinical depressive and anxiety disorders in women
Br. J. Nutr.
Major depression: the importance of clinical characteristics and treatment response to prognosis
Depress. Anxiety
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