Clinical Study | Open Access
Robert K. McNamara, Ronald Jandacek, Therese Rider, Patrick Tso, Yogesh Dwivedi, Ghanshyam N. Pandey, "Adult Medication-Free Schizophrenic Patients Exhibit Long-Chain Omega-3 Fatty Acid Deficiency: Implications for Cardiovascular Disease Risk", Cardiovascular Psychiatry and Neurology, vol. 2013, Article ID 796462, 10 pages, 2013. https://doi.org/10.1155/2013/796462
Adult Medication-Free Schizophrenic Patients Exhibit Long-Chain Omega-3 Fatty Acid Deficiency: Implications for Cardiovascular Disease Risk
Deficiency in long-chain omega-3 (LCn − 3) fatty acids, eicosapentaenoic acid (EPA, 20:5n − 3) and docosahexaenoic acid (DHA, 22:6n − 3), has been implicated in the pathoetiology of cardiovascular disease, a primary cause of excess premature mortality in patients with schizophrenia (SZ). In the present study, we determined erythrocyte EPA + DHA levels in adult medication-free patients SZ () and age-matched healthy controls (). Erythrocyte EPA + DHA composition exhibited by SZ patients (3.5%) was significantly lower than healthy controls (4.5%, −22%, ). The majority of SZ patients (72%) exhibited EPA+DHA levels ≤4.0% compared with 37% of controls (Chi-square, ). In contrast, the omega-6 fatty acid arachidonic acid (AA, 20:4) (+9%, ) and the AA:EPA + DHA ratio (+28%, ) were significantly greater in SZ patients. Linoleic acid (18:2) was significantly lower (−12%, ) and the erythrocyte 20:3/18:2 ratio (an index of delta6-desaturase activity) was significantly elevated in SZ patients. Compared with same-gender controls, EPA + DHA composition was significantly lower in male (−19%, ) but not female (−13%, ) SZ patients, whereas the 20:3/18:2 ratio was significantly elevated in both male (+22%, ) and female (+22%, ) SZ patients. These results suggest that the majority of SZ patients exhibit low LCn − 3 fatty acid levels which may place them at increased risk for cardiovascular morbidity and mortality.
Patients with schizophrenia (SZ) have two- to three-fold higher mortality rates compared with the general population, corresponding to an average 15-year reduction in life expectancy, and cross-sectional epidemiological studies have found that cardiovascular disease is a primary cause of excess premature mortality in SZ patients [1–6]. The etiology of elevated cardiovascular risk in SZ is likely multifactorial, potentially involving excessive smoking and alcohol use, lack of exercise, and poor diets [7, 8]. Moreover, second generation antipsychotic (SGA) medications are associated with cardiovascular risk factors including dyslipidemia, metabolic syndrome, and weight gain [9–13], though these risk factors have also been reported in SGA-naïve first-episode SZ patients [14–16]. Together, these data highlight an urgent need to identify risk and resilience factors associated with elevated cardiovascular disease risk in SZ.
An emerging body of evidence suggests that low levels of long-chain omega-3 (LCn − 3) fatty acids, principally eicosapentaenoic acid (EPA, 20:5n − 3) and docosahexaenoic acid (DHA, 22:6n − 3), are a modifiable risk factor for cardiovascular disease . Mammals are entirely dependent on their diet to obtain LCn − 3 fatty acids, and erythrocyte EPA + DHA composition is positively correlated with habitual dietary LCn − 3 fatty acid intake [18–20]. It is relevant, therefore, that in Japan, where the prevalence of cardiovascular mortality among men is 6-fold lower than in the United States (USA) , annual seafood consumption is 3-fold greater than in the USA  and is associated with ~2-fold greater erythrocyte EPA + DHA levels [23, 24]. Prospective studies have found that erythrocyte EPA + DHA composition (“omega-3 index”) ≤4% of total fatty acids is associated with a 10-fold greater risk for sudden cardiac arrest compared with >8% EPA + DHA composition . Additionally, patients with acute coronary syndrome (ACS) exhibit significantly lower erythrocyte EPA + DHA levels compared with healthy controls . Erythrocyte EPA + DHA composition is positively correlated with human myocardium biopsy EPA + DHA composition , and a cardiac biopsy study found that patients that died from cardiovascular disease exhibited lower heart DHA levels compared with patients dying from noncardiac causes . Together, these and other data suggest that low dietary LCn − 3 fatty acid intake represents a modifiable risk factor for cardiovascular disease in the general population, and that erythrocyte EPA + DHA composition represents a valid risk biomarker for cardiovascular morbidity and mortality.
Several previous case-control studies have observed lower erythrocyte DHA levels in medication-naive SZ patients [29–34]. Emerging clinical evidence suggests that chronic exposure to SGA medications partially normalize erythrocyte DHA deficits in first-episode SZ patients [29, 30, 32, 34] and in the postmortem prefrontal cortex of SZ patients . Preclinical evidence further suggests that chronic treatment with SGA medications increases rat erythrocyte and heart EPA + DHA composition by augmenting biosynthesis [36, 37]. Furthermore, preclinical and clinical evidence suggests that ovarian hormones augment LCn − 3 fatty acid biosynthesis and erythrocyte DHA composition [38–41], and that erythrocyte  and postmortem brain  DHA deficits are more robust in male than female SZ patients. The primary objective of the present study was to compare erythrocyte EPA + DHA composition in adult medication-free male and female SZ patients and healthy controls. Based on cross-sectional evidence that SZ patients are at higher risk than the general population for developing cardiovascular disease, our specific prediction was that erythrocyte EPA + DHA composition would be significantly lower in SZ patients.
2. Materials and Methods
2.1. Subject Demographics
These studies were conducted in hospitalized male and female patients with SZ () admitted to the Psychiatric Clinical Research Center, as part of the General Clinical Research Center (GCRC), University of Illinois at Chicago. Healthy adult male and female controls with no history of psychiatric illness () were recruited from the greater Chicago area. A comparison of group demographic variables is presented in Table 1. Patients were kept medication-free for up to 2 weeks prior to blood collection to permit sufficient washout of antipsychotic medications. Data regarding smoking status, diet, and body mass index were not obtained. This study was approved by the Institutional Review Board of the University of Illinois at Chicago.
AS: Asian, AA: African American, H: Hispanic, C: Caucasian.
PANSS: positive and negative symptom scale.
2.2. Erythrocyte Fatty Acid Composition
Whole venous blood (40 mL) was collected into tubes containing 4 mL of sodium citrate (3.8%) and centrifuged at 210 ×g for 15 min at 4°C. Plasma and the platelet-rich interface were removed, and erythrocytes were washed twice with 0.9% saline and stored at −80°C. Erythrocyte membrane total fatty acid composition was determined with a Shimadzu GC-2014 (Shimadzu Scientific Instruments Inc., Columbia, MD, USA) using the saponification and methylation procedure described previously . Analysis of fatty acid methyl esters was based on area under the curve calculated with Shimadzu Class VP 4.3 software. Fatty acid identification was based on retention times of authenticated fatty acid methyl ester standards (Matreya LLC Inc., Pleasant Gap, PA, USA). Data are expressed as weight percent of total fatty acids (mg fatty acid/100 mg fatty acids). All samples were processed by a technician blinded to group identity. Our primary measure of interest was EPA + DHA. We also determined erythrocyte indices of delta9-desaturase activity (stearoyl-CoA desaturase, 16:1/16:0 and 18:1/18:0 ratios), delta6-desaturase (20:3n − 6/18:2n − 6), delta5-desaturase (20:4n − 6/20:3n − 6), and an index of “de novo lipogenesis” (16:0/18:2).
2.3. Statistical Analysis
Group differences in erythrocyte fatty acid composition were evaluated with unpaired t-tests (2-tailed) and corrected for multiple comparisons (). The distribution of fatty acids was examined for normality using Bartlett’s test. Categorical data were evaluated with the Chi-square test. Parametric (Pearson) correlation analyses were performed to determine relationships between fatty acids and fatty acid ratios (2-tail, ). Effect size was calculated using Cohen’s d. Analyses were performed using GB-STAT (V.10, Dynamic Microsystems, Inc., Silver Springs, MD, USA).
Erythrocyte samples from two SZ patients were excluded from the final analyses because of evidence for gross abnormalities in membrane fatty acid composition, including the absence of DHA. The fatty acid composition of erythrocytes from SZ patients () and healthy controls () are presented in Table 2. Consistent with our a priori hypothesis, erythrocyte EPA + DHA composition (“omega-3 index”) was significantly lower in SZ patients compared with controls (−22%, , ). This difference was attributable to lower DHA (−21%, ) and EPA composition (−24%, ). There were no significant group differences for saturated fatty acids (16:0, 18:0) or monounsaturated fatty acids (16:1n − 7, 18:1n − 7, 18:1n − 9). Among the omega-6 fatty acids, linoleic acid (18:2n − 6) was significantly lower in SZ patients (−12%, , ), and arachidonic acid (AA, 20:4n − 6) (+9%, , ) and docosapentaenoic acid (22:5n − 6) (+19%, , ) were significantly greater in SZ patients. Erythrocyte AA/DHA (+27%, , ) and AA/EPA + DHA (+28%, , ) ratios, but not the AA/EPA ratio (), were significantly greater in SZ patients.
|Weight percent total fatty acids (g/100 g) expressed as mean ± SEM.|
values from the -tests (2-tail).
nd: not detected (below the limit of reliable detection).
The erythrocyte 20:3/18:2 ratio, an index of delta6-desaturase activity, was significantly greater in SZ patients (+20%, , ) (Figure 1(a)), whereas the 20:4/20:3 ratio, an index of delta5-desaturase activity, did not differ between groups () (Figure 1(b)). There were no significant group differences in the 16:1/16:0 () (Figure 1(c)) and 18:1/18:0 () ratios (Figure 1(d)), indices of delta9-desaturase (stearoyl-CoA desaturase) activity. The erythrocyte 16:0/18:2 ratio, an index of do novo lipogenesis, was significantly greater in SZ patients (+16%, ). Among SZ patients (), EPA + DHA was not significantly correlated with the 20:3/18:2 ratio (, ), the 20:4/20:3 ratio (, ), the 16:1/16:0 ratio (, ), the 18:1/18:0 ratio (, ), or the 18:2/16:0 ratio (, ). Among healthy controls (), EPA + DHA was not significantly correlated with the 20:3/18:2 ratio (, ), the 20:4/20:3 ratio (, ), the 16:1/16:0 ratio (, ), the 18:1/18:0 ratio (, ), or the 18:2/16:0 ratio (, ). Among all subjects (), EPA + DHA was inversely correlated with the 20:3/18:2 ratio (, ) and was not correlated with other ratios. Among SZ patients (), positive and negative symptom scale (PANSS) total scores were not significantly correlated with DHA (), EPA + DHA (), AA/EPA + DHA (), or the 20:3/18:2 ratio ().
Compared with same-gender controls, EPA + DHA composition was significantly lower in male (−19%, , ) but not female (−13%, ) SZ patients (Figure 2(a)), and the AA/EPA + DHA ratio was significantly higher in male (+22%, , ) but not female (+19%, ) SZ patients (Figure 2(b)). Compared with same-gender controls, the 20:3/18:2 ratio was significantly greater in both male (+22%, , ) and female (+22%, , ) SZ patients (Figure 2(c)). In healthy controls, EPA + DHA composition (), the AA/EPA + DHA ratio (), and the 20:3/18:2 ratio () did not differ between males and females.
The majority of SZ patients (72%) exhibited erythrocyte EPA + DHA levels ≤4.0% compared with 37% of controls (Chi-square, ) (Figure 3(a)), indicating a 2-fold greater number of SZ patients exhibit an erythrocyte EPA + DHA level of ≤4.0% compared with controls. A comparison of the omega-3 index in adult SZ patients residing in the USA, adult US patients with acute coronary syndromes (ACS, , from ), healthy adults (HA) residing in the USA (, from ), and healthy adults residing in Japan (; from ) is presented in Figure 3(b).
There is now substantial evidence that lower erythrocyte EPA + DHA composition (the “omega-3 index”) is a modifiable risk factor for cardiovascular disease , a primary cause of excess premature mortality in patients with SZ. Consistent with our a priori hypothesis, erythrocyte EPA + DHA composition exhibited by SZ patients (3.5% ± 1.1%) was significantly lower than healthy controls (−22%, 4.5% ± 1.1%, ). These findings are consistent with other cross-sectional studies demonstrating that SZ is characterized by LCn − 3 fatty acid deficits [29–34]. Erythrocyte EPA + DHA composition exhibited by healthy controls is similar to that previously reported in a larger cohort of healthy subjects residing in the U.S. (4.9% ± 2.1%) . Prospective studies suggest that erythrocyte EPA + DHA composition of ≤4% is associated with a 10-fold greater risk for sudden cardiac death compared with ≥8% . In the present study, a greater number (2-fold) of SZ patients exhibit an erythrocyte EPA + DHA level of ≤4.0% compared with healthy controls. This biomarker therefore suggests that the majority of SZ patients in the present study are at elevated risk for cardiovascular morbidity and mortality. Lastly, erythrocyte EPA + DHA composition was significantly lower in male (−19%, ) but not female (−13%, ) SZ patients compared with same-gender controls.
This study has three principal limitations. First, data regarding habitual dietary LCn − 3 fatty acid intake was not available to evaluate its contribution to the erythrocyte EPA + DHA deficits observed in SZ patients. However, several studies have found that erythrocyte EPA + DHA composition is highly positively correlated with habitual dietary EPA + DHA intake [18–20, 23, 24] and that supplementing the diet with LCn − 3 fatty acids increases erythrocyte EPA + DHA composition in SZ patients . Second, data regarding cigarette smoking status was not available, and some prior studies [44–46], but not others [23, 47], have observed an inverse relationship between cigarette smoking and erythrocyte EPA and DHA composition in different populations. However, a radio-tracer study found that cigarette smoking was associated with greater EPA + DHA biosynthesis and plasma availability , and plasma EPA + DHA is positively correlated with erythrocyte EPA + DHA composition . While the objective of this study was not to determine the cause of the EPA + DHA deficits, it remains possible that the erythrocyte EPA + DHA deficits observed in SZ patients are associated with dietary EPA + DHA insufficiency and/or cigarette smoking. Third, the small number of SZ patients used in the present study may not be representative of all patients with SZ. However, the results of the present study are very consistent with prior case-control studies [29–34], and effect sizes were typically large (). Nevertheless, additional studies are warranted to replicate and extend these findings in a different sample of SZ patients.
Prior preclinical and clinical evidence suggests that ovarian hormones augment LCn − 3 fatty acid biosynthesis and erythrocyte EPA + DHA composition [38–41], and reduced levels of circulating estrogen levels were observed in male first-episode psychotic patients . Consistent with prior studies [23, 31], erythrocyte EPA + DHA composition did not differ between healthy male and female controls. However, we did find compared with same-gender controls that EPA + DHA composition was significantly lower in male (−19%, ) but not female (−13%, ) SZ patients. This finding is consistent with a prior study reporting that male (−21%) but not female (−12%) medication-naïve first-episode psychotic patients exhibited significant erythrocyte EPA + DHA deficits compared with same-gender controls . This is also consistent with a prior study finding that male (−27%) but not female (−2%) SZ patients exhibit significant DHA deficits in postmortem prefrontal cortex . It is relevant therefore that SGA-treated male SZ patients exhibit a 1.5-fold greater 10-year cardiovascular risk compared with female SZ patients , though other epidemiological data suggest that cardiovascular disease is the primary cause of excess mortality in female SZ patients whereas suicide is the primary cause of excess mortality in male SZ patients . In view of prior evidence that low DHA levels are also associated with increased suicide risk [50, 51], elucidation of the interrelationship between circulating estrogen levels, tissue DHA concentrations, and cardiovascular and suicide risk may provide important insight into mechanisms contributing to higher premature mortality rates in male and female SZ patients.
Prior case-control studies have observed lower erythrocyte 18:2n − 6 levels in patients with acute coronary syndromes , and the present study found lower erythrocyte 18:2n − 6 levels in SZ patients. While this deficit may be due to lower 18:2n − 6 intake , it may also be a consequence of elevated liver delta6-desturase activity for which 18:2n − 6 is a substrate. For example, we previously reported that elevated liver delta6-desturase activity and expression in response to dietary n − 3 fatty acid deficiency was associated with lower erythrocyte and liver 18:2n − 6 levels despite comparable dietary 18:2n − 6 intake . In the present study, the 20:3/18:2 ratio was significantly elevated in both male and female SZ patients, though the 20:3/18:2 ratio was not correlated with EPA + DHA in SZ patients. Taken in conjunction with our previous finding that delta6-desturase (FADS2) mRNA expression is significantly elevated in the frontal cortex of male and female SZ patients , these data suggest that male and female SZ patients both exhibit elevated delta6-desturase activity. Importantly, elevated indices of delta6-desturase activity were previously found to be positively associated with dyslipidemia, insulin resistance and obesity [55, 56], elevated proinflammatory signaling [57–59], and cardiovascular disease morbidity and mortality [60–62]. These data suggest that elevated delta-6 desaturase activity may also contribute risk for cardiovascular disease in male and female SZ patients.
The low EPA + DHA status of SZ patients may also have implications for resilience to SGA-induced hypertriglyceridemia. For example, concomitant treatment with EPA  or EPA + DHA  significantly decreased elevated triglyceride levels in SZ patients treated with the SGA clozapine. We recently reported that dietary-induced LCn − 3 fatty acid insufficiency leading to deficits in erythrocyte and liver EPA + DHA composition significantly augmented SGA-induced triglyceride accumulation (hepatic steatosis) and plasma triglyceride levels in rats . Human erythrocyte and liver EPA + DHA levels are positively correlated , and patients with hepatic steatosis and/or obesity exhibit significantly lower liver and erythrocyte EPA + DHA levels [66–68]. Interestingly, unlike SZ patients residing in the USA, SGA-treated SZ patients residing in Japan, where erythrocyte EPA + DHA levels are ~2-fold greater than the USA [23, 24], do not exhibit hypertriglyceridemia or obesity . Moreover, cardiovascular disease is a leading cause of excess mortality for SZ patients residing in western countries [1–6] but not Japan . Together, these data suggest that the low LCn − 3 fatty acid status observed in SZ patients residing in western countries may represent a modifiable risk factor for SGA-induced weight gain, hypertriglyceridemia, and associated risk for developing cardiovascular disease.
The present findings also have implications for brain function and associated psychopathology . DHA is the primary LCn − 3 fatty acid in mammalian brain, and nonhuman primate  and human postmortem  studies suggest that cortical and erythrocyte DHA levels are positively correlated. We reported that SZ patients exhibit significant postmortem prefrontal cortex DHA deficits , and emerging evidence from magnetic resonance imaging studies suggest that peripheral (erythrocyte, plasma phospholipids) DHA status is correlated with resting and functional cortical activity [74, 75] and indices of membrane turnover . Moreover, prior studies have found that erythrocyte DHA levels are inversely correlated with negative symptom severity in SZ patients [29, 34, 43], and correction of DHA deficiency reduced positive and negative symptom severity and delayed or prevented the onset of psychosis in ultra high-risk adolescents . In the present study, erythrocyte DHA was not significantly correlated with PANSS total score, though this may be due to limited power. It is also relevant that a controlled trial found that adjunctive treatment with EPA accelerated treatment response and permitted a 20% reduction in SGA dose in first-episode psychotic patients .
In summary, the present case-control study demonstrates that medication-free adult SZ patients exhibit significant erythrocyte EPA + DHA deficits. Based on prior cross-sectional and prospective evidence, the present data suggest that the low EPA + DHA status exhibited by SZ patients, particularly male SZ patients, places them at increased risk for developing acute coronary syndromes and sudden cardiac arrest, as well as SGA-induced hypertriglyceridemia and hepatic steatosis. It is also noteworthy that EPA + DHA deficits are not unique to SZ, and other psychiatric disorders associated with excess premature mortality due in part to cardiovascular disease, including major depressive disorder and bipolar disorder , are also associated with significant erythrocyte EPA + DHA deficits . Because the erythrocyte EPA + DHA deficits exhibited by SZ patients can be corrected by dietary LCn − 3 fatty acid supplementation, this represents a modifiable risk factor. Indeed, the present data add to a growing body of evidence that supports treating SZ patients with LCn − 3 fatty acids in an effort to reduce cardiovascular morbidity and mortality, as well as improve SGA tolerability and overall illness course. Increasing erythrocyte EPA + DHA composition to ≥8%, which is associated with the greatest protection from cardiovascular morbidity and mortality, would represent an appropriate target and is achievable with a daily EPA + DHA dose of ~2.0 g/d .
Funding for this study was provided in part by National Institute of Health (NIH) Grants MH083924 and AG03617, and a NARSAD Independent Investigator Award (to R. K. McNamara), and NIH Grants DK59630 (to P. Tso) and MH56528 (to G. N. Pandey). The NIH and NARSAD had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
- D. P. J. Osborn, G. Levy, I. Nazareth, I. Petersen, A. Islam, and M. B. King, “Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom's General Practice Research Database,” Archives of General Psychiatry, vol. 64, no. 2, pp. 242–249, 2007.
- S. Brown, “Excess mortality of schizophrenia. A meta-analysis,” British Journal of Psychiatry, vol. 171, pp. 502–508, 1997.
- S. Brown, M. Kim, C. Mitchell, and H. Inskip, “Twenty-five year mortality of a community cohort with schizophrenia,” British Journal of Psychiatry, vol. 196, no. 2, pp. 116–121, 2010.
- R. M. Capasso, T. W. Lineberry, J. M. Bostwick, P. A. Decker, and J. S. Sauver, “Mortality in schizophrenia and schizoaffective disorder: an Olmsted County, Minnesota cohort: 1950–2005,” Schizophrenia Research, vol. 98, no. 1–3, pp. 287–294, 2008.
- U. Osby, N. Correia, L. Brandt, A. Ekbom, and P. Sparén, “Mortality and causes of death in schizophrenia in Stockholm County, Sweden,” Schizophrenia Research, vol. 45, no. 1-2, pp. 21–28, 2000.
- M. T. Tsuang, R. F. Woolson, and J. A. Fleming, “Premature deaths in schizophrenia and affective disorders. An analysis of survival curves and variables affecting the shortened survival,” Archives of General Psychiatry, vol. 37, no. 9, pp. 979–983, 1980.
- S. Brown, J. Birtwistle, L. Roe, and C. Thompson, “The unhealthy lifestyle of people with schizophrenia,” Psychological Medicine, vol. 29, no. 3, pp. 697–701, 1999.
- D. C. Henderson, C. P. Borba, T. B. Daley et al., “Dietary intake profile of patients with schizophrenia,” Annals of Clinical Psychiatry, vol. 18, no. 2, pp. 99–105, 2006.
- D. C. Goff, L. M. Sullivan, J. P. McEvoy et al., “A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls,” Schizophrenia Research, vol. 80, no. 1, pp. 45–53, 2005.
- D. C. Henderson, “Weight gain with atypical antipsychotics: evidence and insights,” Journal of Clinical Psychiatry, vol. 68, no. 12, pp. 18–26, 2007.
- J. M. Meyer, “Effects of atypical antipsychotics on weight and serum lipid levels,” Journal of Clinical Psychiatry, vol. 62, no. 27, pp. 27–34, 2001.
- J. W. Newcomer, “Antipsychotic medications: metabolic and cardiovascular risk,” Journal of Clinical Psychiatry, vol. 68, no. 4, pp. 8–13, 2007.
- S. Weinmann, J. Read, and V. Aderhold, “Influence of antipsychotics on mortality in schizophrenia: systematic review,” Schizophrenia Research, vol. 113, pp. 1–11, 2009.
- M. C. Ryan, P. Collins, and J. H. Thakore, “Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia,” The American Journal of Psychiatry, vol. 160, pp. 284–289, 2003.
- L. M. Spelman, P. I. Walsh, N. Sharifi, P. Collins, and J. H. Thakore, “Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia,” Diabetic Medicine, vol. 24, no. 5, pp. 481–485, 2007.
- S. K. Verma, M. Subramaniam, A. Liew, and L. Y. Poon, “Metabolic risk factors in drug-naive patients with first-episode psychosis,” Journal of Clinical Psychiatry, vol. 70, no. 7, pp. 997–1000, 2009.
- W. S. Harris, “The omega-3 index: from biomarker to risk marker to risk factor,” Current Atherosclerosis Reports, vol. 11, no. 6, pp. 411–417, 2009.
- G. Barceló-Coblijn, E. J. Murphy, R. Othman, M. H. Moghadasian, T. Kashour, and J. K. Friel, “Flaxseed oil and fish-oil capsule consumption alters human red blood cell fatty acid composition: a multiple-dosing trial comparing 2 sources of fatty acid,” American Journal of Clinical Nutrition, vol. 88, no. 3, pp. 801–809, 2008.
- J. Cao, K. A. Schwichtenberg, N. Q. Hanson, and M. Y. Tsai, “Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids,” Clinical Chemistry, vol. 52, no. 12, pp. 2265–2272, 2006.
- K. Fekete, T. Marosvölgyi, V. Jakobik, and T. Decsi, “Methods of assessment of long-chain polyunsaturated fatty acid status in humans: a systematic review 1942,” The American Journal of Clinical Nutrition, vol. 89, pp. 2070–2084, 2009.
- World Health Organization, World Health Statistics Annuals, 1985–1995, WHO, Geneva, Switzerland, 1986–1996.
- World Health Organization, World Health Organization Fish and Fishery Products, World Apparent Consumption Based on Food Balance Sheets (1961–1993) FAO Fisheries Circular, no. 821 Rev. 3, Food and Agriculture Organization, Rome, Italy, 1996.
- S. A. Sands, K. J. Reid, S. L. Windsor, and W. S. Harris, “The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes,” Lipids, vol. 40, no. 4, pp. 343–347, 2005.
- M. Itomura, S. Fujioka, K. Hamazaki et al., “Factors influencing EPA+ DHA levels in red blood cells in Japan,” In Vivo, vol. 22, no. 1, pp. 131–136, 2008.
- W. S. Harris and C. Von Schacky, “The Omega-3 Index: a new risk factor for death from coronary heart disease?” Preventive Medicine, vol. 39, no. 1, pp. 212–220, 2004.
- R. C. Block, W. S. Harris, K. J. Reid, S. A. Sands, and J. A. Spertus, “EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls,” Atherosclerosis, vol. 197, no. 2, pp. 821–828, 2008.
- W. S. Harris, S. A. Sands, S. L. Windsor et al., “Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation,” Circulation, vol. 110, no. 12, pp. 1645–1649, 2004.
- N. Chattipakorn, J. Settakorn, P. Petsophonsakul et al., “Cardiac mortality is associated with low levels of omega-3 and omega-6 fatty acids in the heart of cadavers with a history of coronary heart disease,” Nutrition Research, vol. 29, no. 10, pp. 696–704, 2009.
- M. Arvindakshan, S. Sitasawad, V. Debsikdar et al., “Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients,” Biological Psychiatry, vol. 53, no. 1, pp. 56–64, 2003.
- D. R. Evans, V. V. Parikh, M. M. Khan, C. Coussons, P. F. Buckley, and S. P. Mahadik, “Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 69, no. 6, pp. 393–399, 2003.
- A. Kale, S. Joshi, N. Naphade et al., “Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients,” Schizophrenia Research, vol. 98, no. 1–3, pp. 295–301, 2008.
- M. M. Khan, D. R. Evans, V. Gunna, R. E. Scheffer, V. V. Parikh, and S. P. Mahadik, “Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics,” Schizophrenia Research, vol. 58, no. 1, pp. 1–10, 2002.
- R. D. Reddy, M. S. Keshavan, and J. K. Yao, “Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline,” Schizophrenia Bulletin, vol. 30, no. 4, pp. 901–911, 2004.
- M. M. Sethom, S. Fares, N. Bouaziz et al., “Polyunsaturated fatty acids deficits are associated with psychotic state and negative symptoms in patients with schizophrenia,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 83, no. 3, pp. 131–136, 2010.
- R. K. McNamara, R. Jandacek, T. Rider et al., “Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications,” Schizophrenia Research, vol. 91, no. 1–3, pp. 37–50, 2007.
- R. K. McNamara, J. A. Able, R. Jandacek, T. Rider, and P. Tso, “Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: evidence for augmented biosynthesis,” Schizophrenia Research, vol. 107, no. 2-3, pp. 150–157, 2009.
- R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss, and J. W. Lipton, “Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: relationship with liver delta6-desaturase expression,” Schizophrenia Research, vol. 129, no. 1, pp. 57–65, 2011.
- L. Bakewell, G. C. Burdge, and P. C. Calder, “Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets,” British Journal of Nutrition, vol. 96, no. 1, pp. 93–99, 2006.
- C. E. Childs, M. Romeu-Nadal, G. C. Burdge, and P. C. Calder, “The polyunsaturated fatty acid composition of hepatic and plasma lipids differ by both sex and dietary fat intake in rats,” Journal of Nutrition, vol. 140, no. 2, pp. 245–250, 2010.
- E. J. Giltay, L. J. G. Gooren, A. W. F. T. Toorians, M. B. Katan, and P. L. Zock, “Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects,” American Journal of Clinical Nutrition, vol. 80, no. 5, pp. 1167–1174, 2004.
- R. K. McNamara, J. Able, R. Jandacek, T. Rider, and P. Tso, “Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition,” Psychoneuroendocrinology, vol. 34, no. 4, pp. 532–539, 2009.
- R. K. McNamara, R. Jandacek, T. Rider, P. Tso, Y. Dwivedi, and G. N. Pandey, “Selective deficits in erythrocyte docosahexaenoic acid composition in adult patients with bipolar disorder and major depressive disorder,” Journal of Affective Disorders, vol. 126, no. 1-2, pp. 303–311, 2010.
- M. Arvindakshan, M. Ghate, P. K. Ranjekar, D. R. Evans, and S. P. Mahadik, “Supplementation with a combination of ω-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia,” Schizophrenia Research, vol. 62, no. 3, pp. 195–204, 2003.
- W. S. Harris, J. V. Pottala, S. M. Lacey, R. S. Vasan, M. G. Larson, and Robins SJ, “Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study,” Atherosclerosis, vol. 225, no. 2, pp. 425–431, 2012.
- J. R. Hibbeln, K. K. Makino, C. E. Martin, F. Dickerson, J. Boronow, and W. S. Fenton, “Smoking, gender, and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder,” Biological Psychiatry, vol. 53, no. 5, pp. 431–441, 2003.
- A. C. Salisbury, A. P. Amin, W. S. Harris et al., “Predictors of omega-3 index in patients with acute myocardial infarction,” Mayo Clinic Proceedings, vol. 86, no. 7, pp. 626–632, 2011.
- C. C. Chiu, S. Y. Huang, K. P. Su et al., “Polyunsaturated fatty acid deficit in patients with bipolar mania,” European Neuropsychopharmacology, vol. 13, no. 2, pp. 99–103, 2003.
- R. J. Pawlosky, J. R. Hibbeln, and N. Salem, “Compartmental analyses of plasma essential fatty acids among male and female smokers and nonsmokers,” Journal of Lipid Research, vol. 48, no. 4, pp. 935–943, 2007.
- T. J. Huber, C. Tettenborn, E. Leifke, and H. M. Emrich, “Sex hormones in psychotic men,” Psychoneuroendocrinology, vol. 30, no. 1, pp. 111–114, 2005.
- M. D. Lewis, J. R. Hibbeln, J. E. Johnson, Y. H. Lin, D. Y. Hyun, and J. D. Loewke, “Suicide deaths of active-duty US military and ω-3 fatty-acid status: a case-control comparison,” Journal of Clinical Psychiatry, vol. 72, pp. 1585–1590, 2011.
- M. E. Sublette, J. R. Hibbeln, H. Galfalvy, M. A. Oquendo, and J. J. Mann, “Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk,” American Journal of Psychiatry, vol. 163, no. 6, pp. 1100–1102, 2006.
- R. C. Block, W. S. Harris, K. J. Reid, and J. A. Spertus, “Omega-6 and trans fatty acids in blood cell membranes: a risk factor for acute coronary syndromes?” American Heart Journal, vol. 156, no. 6, pp. 1117–1123, 2008.
- R. Hofacer, T. Rider, R. Jandacek et al., “Omega-3 fatty acid deficiency selectively up-regulates delta6-desaturase expression and activity indices in rat liver: prevention by normalization of omega-3 fatty acid status,” Nutrition Research, vol. 31, pp. 715–722, 2011.
- Y. Liu, R. Jandacek, T. Rider, P. Tso, and R. K. McNamara, “Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition,” Schizophrenia Research, vol. 109, no. 1–3, pp. 113–120, 2009.
- L. M. Steffen, B. Vessby, D. R. Jacobs et al., “Serum phospholipid and cholesteryl ester fatty acids and estimated desaturase activities are related to overweight and cardiovascular risk factors in adolescents,” International Journal of Obesity, vol. 32, no. 8, pp. 1297–1304, 2008.
- E. Warensjö, M. Öhrvall, and B. Vessby, “Fatty acid composition and estimated desaturase activities are associated with obesity and lifestyle variables in men and women,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 16, no. 2, pp. 128–136, 2006.
- M. G. Obukowicz, D. J. Welsch, W. J. Salsgiver et al., “Novel, selective Δ6 or Δ5 fatty acid desaturase inhibitors as antiinflammatory agents in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 287, no. 1, pp. 157–166, 1998.
- W. Stoffel, B. Holz, B. Jenke et al., “Δ6-Desaturase (FADS2) deficiency unveils the role of ω3- and ω6-polyunsaturated fatty acids,” The EMBO Journal, vol. 27, no. 17, pp. 2281–2292, 2008.
- R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss, and J. W. Lipton, “Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 83, no. 4–6, pp. 185–191, 2010.
- G. Malerba, L. Schaeffer, L. Xumerle et al., “SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease,” Lipids, vol. 43, no. 4, pp. 289–299, 2008.
- N. Martinelli, D. Girelli, G. Malerba et al., “FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease,” American Journal of Clinical Nutrition, vol. 88, no. 4, pp. 941–949, 2008.
- E. Warensjö, J. Sundström, B. Vessby, T. Cederholm, and U. Risérus, “Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: a population-based prospective study,” American Journal of Clinical Nutrition, vol. 88, no. 1, pp. 203–209, 2008.
- M. Peet and D. F. Horrobin, “A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms,” Journal of Psychiatric Research, vol. 36, no. 1, pp. 7–18, 2002.
- R. N. Caniato, M. E. Alvarenga, and M. A. Garcia-Alcaraz, “Effect of omega-3 fatty acids on the lipid profile of patients taking clozapine,” Australian and New Zealand Journal of Psychiatry, vol. 40, no. 8, pp. 691–697, 2006.
- R. K. McNamara, I. J. Magrisso, R. Hofacer et al., “Omega-3 fatty acid deficiency augments risperidone-induced hepatic steatosis in rats: positive association with stearoyl-CoA desaturase,” Pharmacological Research, vol. 66, no. 4, pp. 283–291, 2012.
- A. Elizondo, J. Araya, R. Rodrigo et al., “Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients,” Obesity, vol. 15, no. 1, pp. 24–31, 2007.
- J. Araya, R. Rodrigo, L. A. Videla et al., “Increase in long-chain polyunsaturated fatty acid / ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease,” Clinical Science, vol. 106, no. 6, pp. 635–643, 2004.
- T. Burrows, C. E. Collins, and M. L. Garg, “Omega-3 index, obesity and insulin resistance in children,” International Journal of Pediatric Obesity, vol. 6, no. 2, pp. e532–e539, 2011.
- J. Watanabe, Y. Suzuki, T. Sugai et al., “The lipid profiles in Japanese patients with schizophrenia treated with antipsychotic agents,” General Hospital Psychiatry, vol. 34, pp. 525–528, 2012.
- Y. Tokuda, H. Obara, N. Nakazato, and G. H. Stein, “Acute care hospital mortality of schizophrenic patients,” Journal of Hospital Medicine, vol. 3, no. 2, pp. 110–116, 2008.
- R. K. McNamara, “Omega-3 fatty acid deficiency: a preventable risk factor for schizophrenia?” Schizophrenia Research, vol. 130, pp. 96–98, 2011.
- W. E. Connor, M. Neuringer, and D. S. Lin, “Dietary effects on brain fatty acid composition: the reversibility of fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys,” Journal of Lipid Research, vol. 31, no. 2, pp. 237–247, 1990.
- J. D. Carver, V. J. Benford, B. Han, and A. B. Cantor, “The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects,” Brain Research Bulletin, vol. 56, no. 2, pp. 79–85, 2001.
- R. K. McNamara, J. Able, R. Jandacek et al., “Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study,” American Journal of Clinical Nutrition, vol. 91, no. 4, pp. 1060–1067, 2010.
- M. E. Sublette, M. S. Milak, J. R. Hibbeln et al., “Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 80, no. 1, pp. 57–64, 2009.
- A. J. Richardson, S. J. Allen, J. V. Hajnal, I. J. Cox, T. Easton, and B. K. Puri, “Associations between central and peripheral measures of phospholipid breakdown revealed by cerebral 31-phosphorus magnetic resonance spectroscopy and fatty acid composition of erythrocyte membranes,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 25, no. 8, pp. 1513–1521, 2001.
- G. P. Amminger, M. R. Schäfer, K. Papageorgiou et al., “Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial,” Archives of General Psychiatry, vol. 67, no. 2, pp. 146–154, 2010.
- G. E. Berger, T. M. Proffitt, M. McConchie et al., “Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial,” Journal of Clinical Psychiatry, vol. 68, no. 12, pp. 1867–1875, 2007.
- F. Angst, H. H. Stassen, P. J. Clayton, and J. Angst, “Mortality of patients with mood disorders: follow-up over 34–38 years,” Journal of Affective Disorders, vol. 68, no. 2-3, pp. 167–181, 2002.
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