Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders

Abstract

IMPORTANCE A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs). OBJECTIVE To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM. DESIGN, SETTING, AND PARTICIPANTS NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach. INTERVENTIONS A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period. MAIN OUTCOMES AND MEASURES The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better. RESULTS In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test). CONCLUSIONS AND RELEVANCE This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available.

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

“…Though the proposal was deemed premature due to problems with reliability in clinical assessment, the diagnostic construct remains a major subject of research into disease progression-modifying treatments [96]. There have been some clinical trials in CHR populations using prophylactic therapies in an attempt to prevent the conversion to schizophrenia [97,98,99,100,101,102,103,104,105]. These have included the use of omega-3 polyunsaturated fatty acids (PUFAs), anti-psychotic use, and numerous psychosocial and cognitive behavioural interventions.…”

“…The clinical trial on prophylactic PUFA administration [106,111] was not replicated in a very recent multicenter randomized clinical trial showing no significant effect of PUFA on conversion rate of individuals at ultra-high-risk for psychosis [105]. Thus, although inflammation and oxidative stress appear to be involved in developmental predisposition to schizophrenia, there are conflicting results on their involvement in the actual transition to psychosis.…”

Nutritional Psychiatry: Where to Next?

“…Similarly, gastrointestinal barrier dysfunction, food sensitivities, inflammation, and the metabolic syndrome are commonly seen in schizophrenia and this warrants research investigating the possible role of such factors in the genesis and progression of psychotic illnesses, and the potential of dietary interventions addressing immune dysfunction, food sensitivities and gut health in those with psychosis. There are data to suggest that targeting inflammation using nutraceutical approaches can prevent emerging psychotic illnesses (Amminger et al, 2010); however, a recent replication study failed to confirm these findings, pointing to both the imperative to replicate early studies and to some of the methodological challenges involved in doing so (McGorry et al, 2017). …”

Cognitive–behavioural therapy can prevent transition to psychosis in ultra-high-risk participants in the long term

“…For example, a recent study investigated the benefit of adding ω-3 polyunsaturated fatty acids in the treatment of UHR participants, also receiving cognitive–behavioural case management 5. Furthermore, the high proportion of participants lost to follow-up and the low transition rates in this study demand replication with larger samples.…”