Psychotic illnesses, such as schizophrenia, develop gradually, beginning with subtle changes in perceptual experiences and thought processes. These changes evolve into a ‘prodromal’ phase characterised by subthreshold positive symptoms such as infrequent/less intense hallucinations and delusions (Yung, McGorry, et al., 2004). Individuals in the prodromal phase are termed Ultra-High Risk (UHR) (Yung & McGorry, 1996).

Observational studies have identified conversion rates from UHR to psychosis of:

• 17.7% at 6 months,
• 21.7% at 12 months,
• and up to 31.5% over 3 years (Fusar-Poli et al., 2012).

Much research has been dedicated towards preventing the transition from UHR status to psychotic illness (Yung, Phillips, et al., 2004). Eleven trials have assessed the effectiveness of talking therapies and pharmacological interventions, alone or combined, in UHR groups (van der Gaag et al., 2013). From these trials, cognitive behavioural therapy (CBT) and long-chain Omega-3 fatty acids (PUFAs) emerged as effective first-line treatments.

PUFAs were found to be effective not only during the period of treatment (Amminger et al., 2010), but also up to 7 years later (Amminger et al., 2015). These are exciting findings as conventional antipsychotics carry undesirable side-effects and an increased risk of adverse events (Kane & Correll, 2017). In a newly published study (McGorry et al., 2017), the authors attempted to replicate these impressive findings.

Methods

NEURAPRO was a double-blind, placebo-controlled, randomised clinical trial, carried out in ten specialised early psychosis treatment services in Australia, Asia, and Europe between 2010-2014. Over a six-month period, 304 participants (aged 13-40) received treatment with 1.4 g of ω-3 PUFAs (containing 840mg of eicosapentaenoic acid and 560mg of docosahexaenoic acid) or paraffin oil placebo. Both groups also received up to twenty sessions of cognitive behavioural case management (CBCM; a CBT-based intervention).

Participants were clinically assessed using a range of validated measures, including the Brief Psychiatric Rating Scale and the Montgomery-Åsberg Depression Rating Scale (MADRS). The primary outcome was transition to psychosis status at six months. Data were analysed using the intention-to-treat approach, comparing transition rates using survival analysis. To compare between recruitment sites and baseline MADRS scores, the stratified log rank test and Cox regression analysis were used. General linear modelling and linear mixed-effects model analysis were used to compare the secondary outcomes (symptoms and functioning).

The numbers lost at follow-up included 39 people from the PUFAs group and 40 in the placebo group. Rates of adherence were also similarly low across groups (approximately 42%). Antidepressants were allowed for treating depression.

Results

• At 6 months, the transition rates were:
  • 6.7% (95% CI, 2.3% to 10.8%) in the PUFAs group
  • 5.1% (95% CI, 1.3% to 8.7%) in the placebo group
• At 12 months, the transition rates were:
  • 11.5% (95% CI, 5.8% to 16.9%) in the PUFAs group
  • 11.2% (95% CI, 5.5% to 16.7%) in the placebo group
• There was no significant difference between PUFAs and placebo in transition rate (P = 0.76). This lack of significance remained even when stratified by recruitment site and baseline MADRS score (P = 0.76).
• No statistically significant difference was noted between the groups in any of the secondary measures (symptoms and functioning) at month 12, or any adverse events.

Discussion

Although ω-3 PUFAs were well tolerated, they were not found to be more effective than placebo in the prevention of psychosis at the six or twelve-month follow-ups. The results show a failure to replicate the previous trial (Amminger et al., 2010). Given the high quality of the study, the most likely explanation is that ω-3 PUFAs are not effective for preventing the transition to psychosis in UHR individuals.

Nonetheless, the authors suggest some caveats. Firstly, both groups received CBCM, which may have created a ‘ceiling effect’ where PUFAs could not create any further benefit. Secondly, there was a high proportion of participants taking antidepressant medication (62% versus 10% in the original study). Studies have suggested that antidepressants may decrease the transition rate in UHR populations (Fusar-Poli et al., 2015), so this may have contributed to the low transition rate across groups.

Finally, in the original trial, PUFA change was measured in participants pre- and post-treatment and found to correlate with functional improvement. This study did not provide such information. PUFAs are thought to help protect neuronal membrane integrity and normalise inflammatory markers (Smesny et al., 2014). Therefore, PUFAs may only be beneficial for a specific subgroup of UHR individuals. This study used a non-specific enrolment strategy, looking at general impairment in relation to symptoms, possibly meaning the subgroup targeted by PUFAs were not well represented (Kane & Correll, 2017).

According to the editorial published alongside (Kane & Correll, 2017), a nine-site replication study in the USA is nearing completion, while another nine-site trial is due to begin in Europe. This is good news, but as the authors state, these trials will not be selecting participants based on the expected biological target of PUFAs either.

Conclusions

This study shows the enormous value of replication. While it may be costly, time-consuming, and (currently) less attractive to high-ranking journals, it increases the credibility of the published scientific literature (Munafò et al., 2017).

The authors conclude:

This trial has failed to replicate the findings of a previous single-centre study. Other multi-centre trials, ongoing analysis of the data from the present study, and future research will help to ultimately determine whether ω-3 PUFAs have a role in the reduction of risk and early treatment of psychotic disorder.

Strengths and limitations

• While not the first trial of PUFAs, it is the first to be randomized, placebo-controlled, multi-centred, and combined with a CBT-derived treatment.
• The authors used inter-rater reliability testing, standardised interviewing, and case review to ensure that participants met criteria for transition.
• ω-3 PUFAs supplements are commercially available, and it is not known whether participants took them outside of the study.
• These supplements are potentially effective for use in depression with high levels of neuronal inflammation. The authors plan to address this by conducting subgroup analyses using baseline membrane fatty acid levels and inflammatory markers.
• Some participants may not truly have been at risk of transitioning to psychosis, although transition rates in PUFAs group were similar to that observed in previous trials, making this unlikely.
• There were relatively low adherence rate in both groups.
• Data was collected at ten specialty clinics, which may not be representative of the care that most UHR individuals receive.

Links

Primary papers

McGorry PD, Nelson B, Markulev C, Yuen HP, Schäfer MR, Mossaheb N, Schlögelhofer M, Smesny S, Hickie IB, Berger GE. (2017). Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial. JAMA Psychiatry, 74(1), 19-27. [Abstract]

Kane, J. M., & Correll, C. U. (2017). ω-3 Polyunsaturated Fatty Acids to Prevent Psychosis: The Importance of Replication Studies (Editorial). JAMA Psychiatry, 74(1), 11-12. [Article]

Other references

Amminger, G. P., Schäfer, M. R., Papageorgiou, K., Klier, C. M., Cotton, S. M., Harrigan, S. M., Mackinnon, A., McGorry, P. D., & Berger, G. E. (2010). Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Archives of general psychiatry, 67(2), 146-154. [PubMed abstract]

Amminger, G. P., Schäfer, M. R., Schlögelhofer, M., Klier, C. M., & McGorry, P. D. (2015). Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nature communications, 6. [PubMed abstract]

Fusar-Poli, P., Bonoldi, I., Yung, A. R., Borgwardt, S., Kempton, M. J., Valmaggia, L., Barale, F., Caverzasi, E., & McGuire, P. (2012). Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk. Archives of general psychiatry, 69(3), 220-229.[PubMed abstract]

Fusar-Poli, P., Frascarelli, M., Valmaggia, L., Byrne, M., Stahl, D., Rocchetti, M., Codjoe, L., Weinberg, L., Tognin, S., & Xenaki, L. (2015). Antidepressant, antipsychotic and psychological interventions in subjects at high clinical risk for psychosis: OASIS 6-year naturalistic study. Psychological medicine, 45(06), 1327-1339. [Abstract]

Munafò, M. R., Nosek, B. A., Bishop, D. V., Button, K. S., Chambers, C. D., du Sert, N. P., Simonsohn, U., Wagenmakers, E.-J., Ware, J. J., & Ioannidis, J. P. (2017). A manifesto for reproducible science. Nature Human Behaviour, 1, 0021.

Smesny, S., Milleit, B., Hipler, U., Milleit, C., Schäfer, M., Klier, C., Holub, M., Holzer, I., Berger, G., & Otto, M. (2014). Omega-3 fatty acid supplementation changes intracellular phospholipase A2 activity and membrane fatty acid profiles in individuals at ultra-high risk for psychosis. Molecular psychiatry, 19(3), 317-324. [PubMed abstract]

van der Gaag, M., Smit, F., Bechdolf, A., French, P., Linszen, D. H., Yung, A. R., McGorry, P., & Cuijpers, P. (2013). Preventing a first episode of psychosis: meta-analysis of randomized controlled prevention trials of 12month and longer-term follow-ups. Schizophrenia research, 149(1), 56-62. [PubMed abstract]

Yung, A. R., & McGorry, P. D. (1996). The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophrenia bulletin, 22(2), 353-370. [PDF]

Yung, A. R., McGorry, P. D., McFarlane, C. A., Jackson, H. J., Patton, G. C., & Rakkar, A. (2004). Monitoring and care of young people at incipient risk of psychosis. Focus.

Yung, A. R., Phillips, L. J., Yuen, H. P., & McGorry, P. D. (2004). Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophrenia research, 67(2), 131-142. [PubMed abstract]

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