Effects of omega-3 PUFA on the vitamin E and glutathione antioxidant defense system in individuals at ultra-high risk of psychosis

Highlights

• Omega-3 PUFA with alpha-tocopherol have a weak (at a trend level) influence on the vitamin E and the glutathione AODS.

• Our findings in terms of the vitamin E AODS suggest direct support of the antioxidative defense at membrane level.

• This mechanism could underlay the clinical effectiveness of the verum condition.

Abstract

Background

Oxidative stress and impaired antioxidant defenses are reported in schizophrenia and are associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, increased negative symptoms, and cognitive impairment. There is evidence that oxidative stress predates the onset of acute psychotic illness. Here, we investigate the effects of omega-3 PUFA on the vitamin E and glutathione antioxidant defense system (AODS).

Method

In 64 help-seeking UHR-individuals (13–25 years of age), vitamin E levels and glutathione were investigated before and after 12 weeks of treatment with either 1.2 g/d omega-3 (PUFA-E) or saturated fatty acids (SFA-E), with each condition also containing 30.4 mg/d alpha-tocopherol to ensure absorption without additional oxidative risk.

Results

In multivariate tests, the effects on the AODS (alpha-tocopherol, total glutathione) were not significantly different (p=0.13, p=0.11, respectively) between treatment conditions. According to univariate findings, only PUFA-E caused a significant alpha-tocopherol increase, while PUFA-E and SFA-E caused a significant gamma- and delta-tocopherol decrease. Total glutathione (GSHt) was decreased by PUFA-E supplementation.

Conclusion

Effects of the PUFA-E condition on the vitamin E and glutathione AODS could be mechanisms underlying its clinical effectiveness. In terms of the vitamin E protection system, PUFA-E seems to directly support the antioxidative defense at membrane level. The effect of PUFA-E on GSHt is not yet fully understood, but could reflect antioxidative effects, resulting in decreased demand for glutathione. It is still necessary to further clarify which type of PUFA/antioxidant combination, and in which dose, is effective at each stage of psychotic illness.

Introduction

Oxidative stress corresponds to an imbalance between the production of reactive oxygen species, including lipid peroxyl radicals, and protective mechanisms. It occurs when the production of oxidants exceeds local antioxidant capacity. Due to the high levels of polyunsaturated fatty acids (PUFA) in the human brain, its high oxidative metabolic demands and its comparatively poor endowment with antioxidant defense systems (AODS), the brain is considered as being at higher risk for oxidative stress [1]. Oxidative stress and alterations of the AODS are involved in the pathophysiology of schizophrenia [2], [3], [4], [5], [6] and other mental disorders, including (Asperger syndrome [7], autism [8], bipolar disorder [9], unipolar depression [10], causing lipid peroxidation, DNA and protein damage [11].

In particular, in first-episode schizophrenia, diverse biomarkers indicate increased oxidative stress [12], [13], [14], [15], [16], while in terms of AODS, a recent meta-analysis disclosed state- and trait-related alterations of antioxidant pathways [6]. In schizophrenia research, a major target of animal and clinical studies is glutathione (GSH) [17], the major cellular redox regulator and antioxidant [18]. GSH has been found to be decreased in the dorsolateral prefrontal cortex, cerebrospinal fluid and post mortem brain tissue of patients [19], [20]. In first-episode patients in particular, total and reduced GSH were found to be significantly decreased, while oxidized glutathione and glutathione peroxidase activity were increased [15], [21], [22] (meta-analysis by Zhang et al. [23]; reviews by Ciobica et al. [24] and Morris et al. [25]).

Vitamin E is an effective chain-breaking lipid-soluble antioxidant [26]. This antioxidant property of vitamin E is believed to be based on its capability for scavenging lipid radicals in the course of the initiation and propagation of lipid peroxidation [27]. Vitamin E in particular protects the PUFA in the phospholipids of biological membranes and in plasma lipoproteins against peroxidation [28]. The steady-state concentrations of vitamin E in membranes are determined by the efficiency of its incorporation into membranes by transfer from blood lipoproteins and its metabolism in these membranes [27]. It is notable that in acutely ill patients with schizophrenia low levels of PUFA were significantly linked to low levels of vitamin E (alpha-tocopherol, other tocopherols were not measured), interpreted as increased consumption because of increased oxidative stress [29]. However, in this study biomarkers of lipid peroxidation (s-TBARS, ery-F2-isoprostane) were not increased. On the other hand, other groups reported associations between decreased PUFA levels and increase levels of lipid peroxides as well as increased severity of negative symptoms [13], [30]. Low vitamin E was also linked to the progression of tardive dyskinesia, and vitamin E was found to have some efficacy in its management.

Based on the findings in first-episode schizophrenia, oxidative stress has been assumed to precede the first acute episode [30], [31]. Evidence for this assumption includes the following: (i) the importance of AODS during neurodevelopment [32]; (ii) the association between oxidative stress and glutamatergic deficits [33], negative symptoms [34] and impaired cognitive functioning [35] all of which are characteristics in the prodromal syndrome; (iii) the occurrence of genetic variants in the AODS in schizophrenia [36], [37], [38], [39]; (iv) the impairment of the AODS in healthy unaffected relatives of psychosis patients [40]; and finally (v) the above-mentioned state/trait marker properties of oxidative stress markers. In fact, markers of oxidative stress/AODS have been recently explored as indicators to identify individuals with impending acute psychosis in ultra-high risk (UHR) populations [41].

When considering the treatment options for UHR individuals, low-dose antipsychotic medication has been found to be of value in delaying or even preventing the onset of psychosis [42]; however, there is ongoing discussion on the risk-benefit profile of these agents [43]. In this context, supplementation with omega-3 PUFA was able to reduce the risk of transition to acute psychosis (4.9% vs. 27.5% respectively), and to improve symptoms and social functioning in UHR individuals without causing side effects [44]. Furthermore, omega-3 PUFA decreased the activity of phospholipase A₂ [45], which acts on oxidatively damaged membrane-bound PUFA [46], [47], [48], and has repeatedly been found to be increased in schizophrenia [49].

As markers of the AODS, our randomized controlled trial in UHR individuals included the vitamin E components alpha-, gamma-, and delta-tocopherol, and glutathione with its metabolites total glutathione (GSHt), reduced glutathione (GSHr), and oxidized glutathione (GSSG). Investigating the effects of omega-3 PUFA or saturated FAs, each in combination with low-dose alpha-tocopherol (i.e., PUFA-E vs. SFA-E), our main hypotheses was:

That only PUFA-E will have a significant effect on the vitamin E and the glutathione AODS, in particular

• that PUFA-E will increase the capacity of vitamin E as a free radical scavenger, measurable as an increase in alpha-tocopherol, and

• that only PUFA-E will rescue the antioxidant GSH pathway, measurable as an increase in GSHt and/or an increase in the GSHr/GSSG ratio.