Omega-3 fatty acid supplementation changes intracellular phospholipase A2 activity and membrane fatty acid profiles in individuals at ultra-high risk for psychosis

Abstract

The identification of an ultra-high risk (UHR) profile for psychosis and a greater understanding of its prodrome have led to increasing interest in early intervention to delay or prevent the onset of psychotic illness. In a randomized placebo-controlled trial, we have identified long-chain ω-3 (ω-3) polyunsaturated fatty acid (PUFA) supplementation as potentially useful, as it reduced the rate of transition to psychosis by 22.6% 1 year after baseline in a cohort of 81 young people at UHR of transition to psychosis. However, the mechanisms whereby the ω-3 PUFAs might be neuroprotective are incompletely understood. Here, we report on the effects of ω-3 PUFA supplementation on intracellular phospholipase A2 (inPLA(2)) activity, the main enzymes regulating phospholipid metabolism, as well as on peripheral membrane lipid profiles in the individuals who participated in this randomized placebo-controlled trial. Patients were studied cross-sectionally (n=80) and longitudinally (n=65) before and after a 12-week intervention with 1.2 g per day ω-3 PUFAs or placebo, followed by a 40-week observation period to establish the rates of transition to psychosis. We investigated inPLA(2) and erythrocyte membrane FAs in the treatment groups (ω-3 PUFAs vs placebo) and the outcome groups (psychotic vs non-psychotic). The levels of membrane ω-3 and ω-6 PUFAs and inPLA(2) were significantly related. Some of the significant associations (that is, long-chain ω-6 PUFAs, arachidonic acid) with inPLA(2) activity were in opposite directions in individuals who did (a positive correlation) and who did not (a negative correlation) transition to psychosis. Supplementation with ω-3 PUFA resulted in a significant decrease in inPLA(2) activity. We conclude that ω-3 PUFA supplementation may act by normalizing inPLA(2) activity and δ-6-desaturase-mediated metabolism of ω-3 and ω-6 PUFAs, suggesting their role in neuroprogression of psychosis.

Polyunsaturated fatty acid biostatus, phospholipase A2 activity and brain white matter microstructure across adolescence

“…It is relevant to note here that PLA 2 activity in serum and CSF are closely correlated (Smesny et al, 2008; Talib et al, 2013). These curvilinear relationships support the notion that there might be an optimum of physiological in PLA 2 activity and membrane LC-UFA turnover associated with healthy WM myelination (Smesny et al, 2014), while excessive in PLA 2 activity may reduce WM myelination. This is in line with findings of increased in PLA 2 activity being associated with structural brain WM abnormalities in patients with schizophrenia including first-episode patients (Smesny et al, 2010).…”

“…Polyunsaturated fatty acids (PUFAs) are important components of the phospholipid bilayers of cell membranes including those of oligodendrocytes. There is active turnover of PUFAs in cellular membranes, which is regulated by intracellular phospholipase A 2 ( in PLA 2 ), a group of enzymes catalyzing the cleavage of fatty acids from the sn-2 position of phospholipids (Smesny et al, 2014). Each PLA 2 enzyme specifically catalyzes the hydrolysis of the center (sn-2)- ester bond of substrate phospholipids and supplies PUFAs downstream to cyclooxygenase and lipoxygenase that in turn transform fatty acids into a group of biomediators called eicosanoids (please see appendix A for additional information on in PLA 2 ).…”

Biomarkers and clinical staging in psychiatry

“…Our own research on the role of intracellular phospholipase A2 (inPLA2) in ultra‐high risk subjects has shown that levels of membrane omega‐3 and omega‐6 PUFAs and inPLA2 activity were strongly correlated. However, some of the significant associations were in opposite directions in individuals who did (a positive correlation) and who did not (a negative correlation) transition to psychosis . These findings are suggestive of ongoing changes in the interactions of membrane metabolic markers during the course of the ultra‐high risk phase of illness (stage 1b).…”

The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors

“…The effectiveness of ω3 fatty acids has also been evaluated in the treatment of bipolar depression, where two of three placebo-controlled, double-blind trials found a beneficial effect over placebo (Clayton et al , 2009, Stoll et al , 1999). This effect may be related to the regulation of intracellular phospholipase A2 activity (Smesny et al, 2013). In addition, ω3 fatty acid treatment was also beneficial in the treatment of schizophrenia (Nakagome et al , 2009, Peet, 2003).…”