Update on Omega-3 Polyunsaturated Fatty Acids in Early-Stage Psychotic Disorders

Polyunsaturated fatty acids (PUFAs) are the major constituents of cell membrane phospholipids. As such, they have multiple important biological roles, including in receptor binding, neurotransmission, signal transduction, and eicosanoid synthesis. A growing body of studies suggests significant reductions in PUFA levels in people with schizophrenia (Berger et al, 2006). Concordant with these findings, fatty acids, particularly the omega-3 PUFA, may have a beneficial role in the treatment of first-episode schizophrenia, and in the prevention of schizophrenia, while results in chronic schizophrenia have been mixed (Peet, 2008). We have recently tested whether supplementation with omega-3 PUFA could reduce the rate of transition to first-episode psychosis in an ultra-high risk (UHR) cohort. In our study, we randomized 81 individuals aged 13–25 years to 12 weeks of either 1.2 g/day of omega-3 PUFA or placebo, followed by a 40-week monitoring period. In all, 2 of 41 (4.9%) of those receiving the active agent transitioned to psychosis, compared with 11 of 40 (27.5%) in the placebo group, a statistically significant difference (Amminger et al, 2010). While PUFAs have been investigated in schizophrenia, their role in the onset of psychotic symptoms is unclear. Therefore, we examined the relationship between omega-3 PUFA (ie, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)) levels in erythrocyte membrane phosphatidylethanolamine and measures of psychopathology in our UHR cohort at baseline. Erythrocyte membrane phospholipid composition closely reflects that of neuronal membranes, and provides an easily accessible indicator of brain phospholipids. While ALA, EPA, and DHA did not correlate significantly with any symptom measure, low levels of DPA and the summary score of all assessed omega-3 fatty acids (ie, ALA, EPA, DPA, and DHA) correlated with more severe negative symptoms. These correlations remained significant after adjustment for potential confounders (ie, age, sex, and nicotine use). Reduced DPA has been previously reported in neuroleptic-naïve first-episode schizophrenia patients (Reddy et al, 2004). Given our intervention study provided support for the ‘dose–response' criterion (McNamara, 2011), as an increase in erythrocyte omega-3 PUFA levels reduced the rate of transition to psychosis and correlated with functional improvement, we tested if the subjects with the lowest erythrocyte omega-3 levels at baseline were at higher risk for transitioning to psychosis. To eliminate treatment effects, we only investigated those participants who had received placebo. Cox regression analyses with adjustment for age, sex, and nicotine use indicated that no single omega-3 PUFA or their summary score predicted conversion to psychosis. Following studies reporting lower levels of arachidonic acid (AA) and nervonic acid (NA), as well as DHA, in people with schizophrenia (Assies et al, 2001), we also examined if these fatty acids predicted transition to psychosis. While AA was not found to be predictive, low NA levels at baseline significantly predicted transition to psychosis (Amminger et al, submitted). As NA is a major constituent of the myelin sheath, low levels of NA could reflect suboptimal myelination in those UHR individuals who develop a psychotic disorder. The finding is consistent with the well-established finding of white matter abnormalities in schizophrenia (Ellison-Wright and Bullmore, 2009). Notably, the observation that supplementation with omega-3 PUFAs may prevent transition to psychosis suggests that omega-3 fatty acids may offset the risk conferred by decreased levels of NA. A randomized controlled multicenter phase III clinical trial of omega-3 PUFA is now underway to replicate the findings (Australian New Zealand Clinical Trials Registry - ACTRN12608000475347).

The authors declare no conflict of interest.