A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia

Abstract

Membrane lipid metabolism and redox regulation may be disturbed in schizophrenia. We examined the clinical effect of adding an omega-3 fatty acid and/or vitamins E+C to antipsychotics. It was hypothesized that lower baseline levels of polyunsaturated fatty acids (PUFAs) would predict more benefit from the add-on treatment. The trial had a multicenter, randomized, double-blind, placebo-controlled 2 × 2 factorial design. Patients aged 18–39 years with schizophrenia or related psychoses were consecutively included at admission to psychiatric departments in Norway. They received active or placebo ethyl-eicosapentaenoate (EPA) 2 g day−1 and active or placebo vitamin E 364 mg day−1+vitamin C 1000 mg day−1 (vitamins) for 16 weeks. The main outcome measures were Positive and Negative Syndrome Scale (PANSS) total and subscales scores, analyzed by linear mixed models. Ninety-nine patients were included. At baseline, erythrocyte PUFA were measured in 97 subjects. Given separately, EPA and vitamins increased drop-out rates, whereas when combined they did not differ from placebo. In low PUFA patients, EPA alone impaired the course of total PANSS (Cohen's d=0.29; P=0.03) and psychotic symptoms (d=0.40; P=0.003), especially persecutory delusions (d=0.48; P=0.0004). Vitamins alone impaired the course of psychotic symptoms (d= 0.37; P=0.005), especially persecutory delusions (d=0.47; P=0.0005). Adding vitamins to EPA neutralized the detrimental effect on psychosis (interaction d=0.31; P=0.02). In high PUFA patients, there were no significant effects of trial drugs on PANSS scales. In conclusion, given separately during an acute episode, EPA and vitamins E+C induce psychotic symptoms in patients with low levels of PUFA. Combined, these agents seem safe.

Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?

“…However, these vitamins have also been given with some success together with 3-omega fatty acids which are key components of membrane phospholipids and have anti-inflammatory properties among others (see reviews: Leza et al, 2014; Muller et al, 2013; Sinn et al, 2010). Interestingly, Bentsen et al (2013) found that vitamins and 3-omega fatty acids, when given separately, can be deleterious in a subgroup of patients. In the present review, we will however focus on NAC because it has antioxidant and anti-inflammatory properties, and can regulate glutamatergic neurotransmission.…”

“…The development of other molecules with better bioavailability and blood-brain barrier permeability are therefore needed. As vitamins C and E or 3-omega fatty acids are detrimental for a subgroup of patients (Bentsen et al, 2013), it would be also advisable using biomarkers to identify patients that would most benefit from an antioxidant treatment. Moreover, NAC or other molecules that target redox, immune, and glutamatergic systems may be more beneficial for young subjects at risk than for chronic patients because the defects in PVI and oligodendrocytes/myelination may precede illness onset.…”

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

“…In a study of patients at high risk of post‐traumatic stress disorder, omega‐3 PUFAs had no effect serum BDNF or mental state (Matsuoka et al, ). Finally, a randomized double‐blind clinical placebo‐controlled trial of add on EPA and/or Vitamins C + E in acute schizophrenia (n = 99) found these agents to worsen psychosis (Bentsen, Osnes, Refsum, Solberg, & Bohmer, ). To explain these discrepancies, groups have postulated omega‐3 PUFAs could have opposing neuroprotective or neurotoxic effects depending upon disease stage, for example, prodromal phase vs acute exacerbation of schizophrenia.…”

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

“…Polyunsaturated fatty acid metabolism deficits have been suggested in psychiatric disorders, and omega-3 fatty acid and vitamins (Vitamin E and C) supplementation have been evaluated as added to antipsychotics, but with mixed findings on symptom reductions (29–31). Docosahexanoic (DHA) (50 mg/kg) or DHA + D-serine (600 mg/kg) had no effect on PCP-induced locomotor activation, but ascorbic acid (300 mg/kg, i.p.)…”