Effect of omega-3 fatty acids for indicated prevention of young patients at risk for psychosis: When do they begin to be effective?

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Abstract

The results of a recent double-blind, randomized, placebo-controlled trial performed in 81 young patients at ultra-high risk for psychosis indicated that a 12-week intervention of 1.2 g/day of ω-3 polyunsaturated fatty acids (PUFA) significantly reduced the risk of transition to psychosis and improved positive, negative and general symptoms as well as functioning. The aim of this post-hoc analysis was to determine at which time point ω-3 PUFAs start to significantly differ from placebo in improving psychopathology and functioning in young people at risk of developing psychosis. Analyses were performed using the mixed model repeated-measures analysis of variance. Compared to placebo, ω-3 PUFAs' significant effects on the amplitude of the reduction in General and Total PANSS scores are evident after the first four weeks of treatment; a reduction of positive symptoms and a lower mean PANSS positive score were apparent after eight weeks, whereas the significant drop in negative symptoms and the significant change and higher mean scores in global functioning occur later at 12 weeks. The delay of onset of ω -3 PUFAs seems comparable to that of antipsychotics and antidepressants.

Introduction

Indicated prevention in adolescents and young adults at ultra-high risk (UHR) of psychosis has been the focus of early intervention research in recent years. To reduce the risk of transition to a full-blown first episode of psychosis, trials have used low-dose antipsychotics (McGorry et al., 2002, McGlashan et al., 2006), cognitive therapy (Morrison et al., 2004, Morrison et al., 2012), the combination of both (Yung et al., 2011), or intensive treatment with family intervention (Nordentoft et al., 2006). Although successful in reducing the risk of psychosis over the short term, trials using antipsychotic medication have not yielded significantly better longer-term results than non-pharmacological treatments, and introduce the risk of short- and long-term side effects (Preti and Cella, 2010). In light of recent findings on glutamate hypermetabolism as a possible firestarter in UHR patients, it is suggested that antipsychotics, which can increase glutamate levels, should be omitted in this patient group (Moghaddam, 2013). Furthermore, prospective longitudinal MRI data in patients with schizophrenia have recently provided evidence that antipsychotic treatment intensity is associated with long-term brain tissue loss (Andreasen et al., 2013). Thus, in the UHR population, with naturalistic transition rates of about 15–30% (Yung et al., 2003, Addington et al., 2007, Riecher-Rössler et al., 2007, Yung et al., 2007), more benign treatments might be more appropriate with respect to efficacy and side effects.

We have recently reported on the effects of long-chain omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) for indicated prevention of psychosis in adolescents and young adults at risk of developing psychosis. The results of this double-blind, randomized, placebo-controlled trial indicated that a 12-week intervention of 1.2 g/day of ω-3 PUFAs significantly reduced the risk of transition to psychosis at one year follow-up (Amminger et al., 2010). The number needed to treat (NNT) with ω-3 PUFAs in the study to prevent one individual from progressing to psychosis during a 12-month period was 4. The ω-3 PUFA group also showed greater improvement in positive, negative and general symptoms as well as in functioning. Interestingly, the protective effects were sustained for the entire 12-month observation period, although the duration of the intervention was only 12 weeks. This effect could be explained by the neuroprotective properties of ω-3 PUFAs (Gama et al., 2012). Indeed, ω-3 PUFAs show an anti-inflammatory action (El-Ansary et al., 2011) and induce antiapoptotic (Calon et al., 2004) as well as antioxidant factors (Kim et al., 2001, Calder, 2003, Calon et al., 2004, El-Ansary et al., 2011, Mossaheb et al., 2012).

Omega-3 PUFAs have the advantage of excellent tolerability, public acceptance, relatively low cost, and benefits for general health (Mozaffarian and Rimm, 2006.). The findings of our trial, while preliminary, might therefore reasonably suggest that psychiatrists recommend ω-3 PUFAs to UHR patients because there are known benefits and little risk associated with this supplementation. To further underpin the importance of lipid biology for the onset of psychosis, we have recently shown that decreased levels of fatty acids may serve as biomarkers predicting psychosis conversion (Amminger et al., 2011), and that lower levels of omega-3 PUFAs are specifically associated with negative symptoms in UHR patients (Amminger and McGorry, 2012). Together these findings raise the question at what time point during such an intervention ω-3 PUFAs begin to show beneficial effects on positive, negative and global symptoms as well as on functioning. Most of the previously published double-blind randomized controlled trials using ω-3 PUFA supplementation in patients with psychosis have used a timeframe of three months, however, the timepoint of onset of effects is not reported (Fenton et al., 2001, Peet et al., 2001, Emsley et al., 2002, Berger et al., 2007). The aim of this post-hoc analysis was to determine at which time point within the 12 weeks of the intervention ω-3 PUFAs start to significantly differ from placebo in improving psychopathology and functioning in young people at UHR of developing psychosis, i.e. at which time point were gains made.

Section snippets

Sample

Patients aged 13–25 years meeting at least one of three operationally defined criteria for increased risk for psychosis (i.e., attenuated psychotic symptoms, brief limited intermittent psychotic symptoms, or a genetic risk with decreased functioning) were included in the study if they did not fulfil any of the exclusion criteria. These included a previous history of a psychotic disorder or manic episode, a substance-induced psychotic disorder, acute suicidal or aggressive behaviour, a current

Results

For the PANSS (Positive and Negative Syndrome Scale, Kay et al., 1987) measures, the omnibus interaction between medication group and occasion was significant for the Total (F6, 158 = 2.37, P = 0.03), General (F6, 165.4 = 2.44, P = 0.03), and Positive (F6, 158.43 = 2.30, P = 0.04) scores. The interaction between medication group and occasion was not significant for the PANSS Negative scores (F6,148.2 = 1.66, P = 0.14).

Planned comparisons indicated that the ω-3 group demonstrated a significantly greater drop in

Discussion

Analysis of the onset of therapeutic action during the 12-week intervention with ω-3 PUFAs in patients fulfilling UHR criteria for psychosis revealed a heterogeneous profile with respect to the different dimensions of psychopathology. Compared to placebo, ω -3 PUFAs' significant effects on the amplitude of the reduction in General and Total PANSS scores are evident after the first four weeks of treatment; a reduction of positive symptoms and a lower mean PANSS positive score is apparent after

Conclusion

In summary, ω-3 PUFAs lead to a seeming temporal cascade of responses with a delay comparable to that of antipsychotic and antidepressant drugs, resulting in longer lasting psychopathological and psychosocial improvements after a supplementation period of only 12 weeks. Because of their favourable risk-benefit profile, many clinicians have been considering ω-3 PUFA supplementation for UHR patients since the publication of the original trial (Amminger et al., 2010). With this in mind, the

Role of the funding source

The study was supported by grant 03 T-315 from the Stanley Medical Research Institute.

Contributors

Author NM contributed to: the literature searches, interpretation of results, and drafted the manuscript.

Authors GPA contributed to: design of the study, supervision, clinical part of the study, data analysis, interpretation of results and writing of the manuscript.

Author MRS, CMK and MS contributed to: clinical part of the study as well as writing of the manuscript.

Author SMC contributed to: data analysis, interpretation of results and writing of the manuscript.

Author PDM contributed to:

Conflict of interest

None of the contributing authors (Nilufar Mossaheb, Miriam R Schaefer, Monika Schloegelhofer, Claudia M Klier, Sue M Cotton, Patrick D McGorry, G. Paul Amminger) have any conflicts of interest to report.

Acknowledgments

Dr G Paul Amminger was supported by grant 566529 from the National Health and Medical Research Council, Australia. We would like to thank Konstantinos Papageorgiou for his assistance with data collection and data entry.

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