Association between Arachidonic Acid and the Risk of Schizophrenia: A Cross-National Study and Mendelian Randomization Analysis

FAB RESEARCH COMMENT:

This new study found that lower dietary intakes of omega-6 AA, but not lower omega-3 DHA intakes, were significantly associated with incidence rates of schizophrenia across the 24 countries studied.  In addition, a role for both omega-6 AA, and omega-6 GLA was supported by Mendelian genetic analyses.

Adequate supplies of both long-chain omega-3 and omega-6 fatty acids (LC-PUFA) are absolutely essential for brain development and function, and deficiencies of both the main omega-6 LC-PUFA, arachidonic acid (AA), and the long-chain omega-3 (EPA and DHA) have repeatedly been reported in patients with schizophrenia.

Furthermore, the observations leading to the original 'membrane hypothesis of schizophrenia' - which first sparked research into the potential benefits of dietary supplementation with LC-PUFA more than 30 years ago - primarily concerned clinical observations consistent with a deficit of omega-6 AA in schizophrenia. 

Findings from this new study provide strong support from these initial, but largely overlooked, observations.

Interest in omega-6 in relation to schizophrenia largely fell away after very early small clinical trials found little or no benefit for schizophrenia symptoms from supplementation with omega-6 fatty acids alone (using evening primrose oil, containing omega-6 GLA - which converts in the body to the more bioactive longer chain omega-6 DGLA, and AA).

Instead, attention switched to the long-chain omega-3 EPA and DHA (found mainly in fish and seafood) - not least because these are more seriously lacking from modern, western-type diets than omega-6 AA (found pre-formed in meat, fish, eggs and dairy fats).

While some clinical trials have shown benefits for patients with schizophrenia (and other forms of psychosis) from supplementation with omega-3 LC-PUFA (particularly EPA), findings have been mixed - with benefits from omega-3 more likely if used early in the course of illness - i.e. in first-episode patients. 

Much more promising data have come from clinical trials of omega-3 for the prevention of psychosis in high-risk individuals - which remains an active area of research.

Meanwhile, however, studies of blood and brain fatty acids in schizophrenia have continued to show deficits of omega-6 AA, as well as omega-3 DHA in this condition.

Furthermore, supplementation with omega-3 EPA alone in schizophrenia has also been reported to increase blood levels of not only omega-3 EPA and DHA (as would be expected), but also omega-6 AA.  And in clinical trials, increased AA was most closely correlated with symptom improvements. 

These new findings suggest that further investigations of the role of omega-6 AA in schizophrenia may be long overdue.