Cross-sectional observational studies
The above epidemiological and biological data on fatty acid metabolism in psychiatric disorders increasingly stimulated research in fatty acid alterations in patients. Cross-sectional studies in several psychiatric disorders generally show associations with a pattern of decreased concentrations of omega-3 fatty acids, and an increased omega-6/omega-3-ratio (Freeman
2000; Haag
2003). Evidence seems to be strongest for major depressive disorder (Lin et al.
2010), but a similar pattern seems to exist for schizophrenia (Hoen et al.
2013). Anxiety disorders are less extensively studied (Ross
2009; de Vries et al.
2016); we previously found lower DHA in PTSD patients compared to controls, but only after correction for diet (de Vries et al.
2016).
Importantly, several negative findings have been published as well (Lin et al.
2010; Hoen et al.
2013; Mocking et al.
2015; Medema et al.
2016). A wide range of methodological issues could explain these inconsistencies. First, statistical methodological issues regarding fatty acid expression and testing may influence reported fatty acid alterations, including correct handling of non-detects, expression of fatty acids in relative percentages or absolute concentrations, and multiple testing problems (Mocking et al.
2012c). For example, using zero-substitution for non-detectable values may artificially lower statistical estimates of mean concentrations. In addition, some studies express fatty acids as relative percentages of the total fatty acid pool, while other studies use absolute concentrations, which may influence the extent of the differences. Finally, given the large number of different fatty acids, multiple testing issues may induce type I errors, for which many studies do not systematically correct (Mocking et al.
2012c).
Second, results may be influenced by the focus on omega-3 and omega-6 PUFAs instead of the overall fatty acid alteration pattern (Assies et al.
2010). Given the unique properties of the essential fatty acids of the omega-3 and -6 subclasses, most studies focused on these fatty acids. Nevertheless, increasing data suggest that fatty acid alterations in psychiatric disorders extend beyond the omega-3 and -6 subtypes, and can also be observed in saturated and monounsaturated fatty acids (Assies et al.
2010; Assies et al.
2014). This suggests patterns of alterations in fatty acids and their oxygenated products that can be better studied using lipidomic or metabolomic approaches as are currently increasingly being applied.
In addition, evidence is available suggesting bimodal distributions of fatty acid concentrations, which may influence statistical interpretations. For example, following observations of bimodal distributions of polyunsaturated fatty acids in schizophrenia (Bentsen et al.
2011), we showed that overall fatty acid unsaturation and chain length were also bimodally distributed in recurrent depression (Mocking et al.
2012b). This bimodal distribution has been suggested to represent two endophenotypes (Bentsen et al.
2011).
Alternatively, the inconsistencies in cross-sectional findings could be explained by confounding, e.g., due to lifestyle or medication use (Assies et al.
2014). This may suggest that the observed association between psychiatric disorders and fatty acid alterations merely reflect epiphenomena of the disease, instead of risk factors. One important lifestyle factor is diet. Not all studies apply standard corrections for dietary intake (Lin et al.
2010). In addition, diet is difficult to measure and residual confounding after correction could still influence results. Nevertheless, it could be questioned whether diet should be seen as a confounder. If differences in dietary intake lead to altered fatty acid concentrations that increase disease risk, fatty acids could instead be seen as mediators of the effect of differences in dietary intake (Assies et al.
2014). A more definitive answer on whether fatty acids should be seen as epiphenomena or risk factors can be found by prospective cohort and intervention studies as described below.
Regarding medication use, several (psychotropic) medications may theoretically affect fatty acid concentrations and intake. Some studies investigated fatty acids exclusively in medication free subjects (Lin et al.
2010; Mocking et al.
2015,
2017a), but in general the precise effects of the different medications on fatty acid concentrations have not been systematically studied in psychiatric patients. Nevertheless, the relation between metabolic alterations and psychiatric diseases was already observed well before the development of psychotropic medication (Assies et al.
2014). Larger samples and individual patient data meta-analyses, providing the opportunity to study the association between medication use and fatty acids in more detail, may yield more insight on the potential confounding effects of medication use.
Furthermore, fatty acid alterations have been mostly studied in peripheral samples, e.g., erythrocyte membranes, given the impossibility of in vivo brain tissue sampling. Nevertheless, (I) blood concentrations generally shown adequate correlations with central measures, as shown in vivo in cerebrospinal fluid, as well as in postmortem and animal studies (Carlson et al.
1986; Connor et al.
1990; Babin et al.
1993; Makrides et al.
1994; Carver et al.
2001; Yao et al.
2002; Cunnane et al.
2012; Jumpertz et al.
2012; Guest et al.
2013), (II) fatty acids both passively and actively cross the blood-brain-barrier (Chen et al.
2008; Mitchell et al.
2011), and (III) findings in post-mortem brains generally corroborate findings from peripheral samples for psychiatric disorders (McNamara and Carlson
2006; Hamazaki et al.
2012; McNamara et al.
2014).
Overall, these cross-sectional findings show a general picture of reduced concentrations of omega-3 fatty acids and an increase in omega-6/omega-3 ratio in at least depression and schizophrenia. Some transdiagnostic studies have aimed to compare fatty acid pattern alterations between psychiatric disorders (Hamazaki et al.
2012; Hamazaki et al.
2015), but evidence is still limited in that regard (Ross et al.
2007).
Longitudinal observational studies
Similar to the above cross-sectional data, prospective studies on the relationship between fatty acids and depression show substantial heterogeneity (Lucas et al.
2011; Grosso et al.
2014; Matsuoka et al.
2017). Although other fatty acid classes have also been prospectively studied, most studies again focused on omega-3 fatty acid concentrations or intake. A meta-analysis of prospective studies showed a protective effect for both fish and EPA + DHA intake on the development of depression over a follow-up of up to 30 years (Grosso et al.
2016). Associations remained after controlling for dietary and socio-economic variables. For omega-3 fatty acid concentrations as biomarkers as opposed to intake, results seem somewhat more inconsistent, with some studies showing a protective association (Beydoun et al.
2015; Berger et al.
2017), and others no relationship (Astorg et al.
2009; Persons et al.
2014). Additional supportive evidence for a prospective relationship comes from studies showing fatty acid alterations that remain during remission (Assies et al.
2010).
Longitudinal data for psychotic disorders show a similar prospective association for both fatty acid intake and concentrations during different stages of the disease (McGorry et al.
2014). Next to protective associations for omega-3 fatty acid intake and concentrations, evidence also exists for a protective effect of omega-9 fatty acid nervonic acid concentrations, a major constituent of myelin membrane sphingolipids (Amminger et al.
2012).