Final Word? Omega-3's Don't Prevent Transition to Psychosis

Pam Harrison

November 30, 2016

Daily consumption of omega-3 polyunsaturated fatty acids (PUFAs) does not appear to prevent transition to psychosis in young patients at ultra–high risk, new research shows. However, investigators say this may not be the final word.

The study findings contradict previous results from the same group of researchers that suggested that PUFAs were superior to placebo in reducing the risk for transition to psychosis, not only while patients were taking the supplement but for a prolonged period thereafter.

"Omega-3's have neuroprotective and anti-inflammatory properties, while gray matter loss and inflammation have been associated with the pathophysiology of schizophrenia, so there is a strong biological rationale why omega-3 PUFAs may improve or prevent a psychotic episode," senior author Paul Amminger, MD, PhD, Orygen Youth Health, the National Center of Excellence in Youth Mental Health, the University of Melbourne, in Australia, told Medscape Medical News.

Dr Amminger was the lead author of both previous studies, which showed a strong protective effect from omega-3 PUFAs in ultra-high-risk patients in a similar prodromal state.

"And it is still possible that omega-3 fatty acid treatment is effective in a subpopulation of ultra-high-risk young people and that the broader group in our study masked this group," he said, adding, however, that the current study "clearly failed to replicate the findings of the original single-center trial."

The study was published online November 23 in JAMA Psychiatry.

Prodromal Patients

NEURAPRO was a randomized, double-blind, placebo-controlled trial involving 304 participants aged 13 to 40 years.

"All participants either had a low level of functioning (Social and Occupational Functioning Assessment Scale [SOFAS] scores <50) sustained for at least a year or had experienced a significant decrease in their functioning (≥30% reduction in their SOFAS score) over the past year," investigators, with first author Patrick McGorry, MD, PhD, from the same national center in Melbourne, note.

Patients were randomly allocated to receive either 6 months of omega-3 PUFAs or placebo. Both groups also received cognitive-behavioral case management (CBCM), and a high proportion of patients received antidepressant therapy for the treatment of depression.

Each capsule of the omega-3 PUFA supplement contained 840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid, for a total of approximately 1.4 g of omega-3 PUFAs per day. Placebo capsules contained paraffin oil.

The mean number of CBCM sessions attended was relatively equivalent, at 11.2 in the omega-3 PUFA group and 10.3 for patients receiving placebo.

Patients were followed for an additional 6 months after discontinuation of active therapy, although they could access CBCM sessions if needed.

At 6 months, 6.7% of patients in the omega-3 PUFA group had transitioned to a psychotic episode, as did 5.1% of control participants. At 12 months, transition rates were 11.5% in the omega-3 PUFA group vs 11.2% for patients receiving placebo.

At month 6, an almost significant improvement was seen in two measures, the Montgomery-Ásberg Depression Rating Scale (MADRS) and the SOFAS scale.

There was also a statistically significant improvement in scores on the Global Functioning: Social and Role scale (P = .02).

"However, the direction of these changes was in favour of the placebo group," the investigators write. They add there was no statistically significant difference between the groups in any of the measures at month 12.

When investigators compared transition rates to psychosis among patients at highest risk for a psychotic episode, as indicated by a MADRS score of 14 or higher, there was again no significant difference in transition rates between the omega-3 PUFA group and patients receiving placebo.

Relatively equal percentages of participants were adherent in both treatment arms. "As expected, the transition rate was lower in the adherent participants," the investigators write.

The difference between the two treatment groups was not significant regardless of participants' level of adherence.

Low Adherence Rate

The researchers acknowledge that the "obvious and most likely" reason that this trial could not reproduce findings of the earlier studies was that omega-3 PUFAs are simply not effective in preventing young patients in a prodromal state from transitioning to psychosis.

On the other hand, "all participants received intensive psychological support for 12 months, which in itself may have improved their psychiatric symptoms and social functioning, preventing any deterioration in their mental health," Dr Amminger noted.

He also stressed that the overall transition rate to psychosis, which was even lower, at 10.5%, when calculated as the proportion of known transitions to psychosis, was substantially lower than the 16.1% transition rate seen in their earlier trial.

This lower transition rate might reflect the fact that both treatment groups received CBCM sessions during the first 6 months of the study.

"Another issue responsible for the lack of efficacy of omega-3 fatty acids was the very low adherence rate: only 42% took 75% or more of the provided capsules, while adherence in the original study was much higher," said Dr Amminger.

Ceiling Effect?

In an accompanying editorial, John Kane, MD, and Christoph Correll, MD, both from the Northwell Health System, Glen Oaks, New York, agreed with the authors that the low conversion rate from the prodromal state to psychosis in the current study represented a major challenge to the analysis of results, as it was very low in both groups.

They also note that antidepressants were also used in more than 60% of the participants in the current study, compared with only 10% in the original trial, in which benefit from omega-3 PUFAs was observed.

"So it may be that there was a 'ceiling effect,' and it was difficult for investigators to show that PUFA had an advantage over placebo," Dr Kane told Medscape Medical News.

Dr Kane cautioned that psychiatrists cannot draw conclusions from any one study, and there is a need to answer the question as to whether or not omega-3 PUFAs have a protective effect against psychosis in ultra-high-risk patients.

Two additional studies of omega-3 PUFAs are either ongoing or are about to begin, and it is hoped that results from these two studies will clarify the role of omega-3 PUFAs in the prevention of psychosis, Dr Kane and Dr Correll point out.

These studies are needed not only because of the low overall transition rate to psychosis in the current trial but also because the use of CBCM in both treatment groups does not reflect "real-world" control conditions, and thus current findings may not be generalizable to the real-world setting, the editorialists note.

"In our field, no one study is ever going to definitely answer a question, so we're definitely looking forward to other studies to try and clarify this question," Dr Kane said.

"But the use of omega-3 PUFAs is an appealing concept — they're safe, and they don't have the kind of side effects we might see with an antipsychotic medication, for example, so were it to be successful, that would be really advantageous," he concluded.

Dr Amminger agreed that additional studies should proceed despite the negative replication trial.

To understand whether PUFAs are effective in a subpopulation of ultra-high-risk patients, the investigators are analyzing levels of inflammatory markers and omega-3 fatty acids in the blood of each study participant both before and at the end of the study's treatment phase to determine whether these biomarkers correlate with the participants' level of psychiatric symptoms at study outset and conclusion.

Dr Amminger and colleagues at Orygen are currently conducting a National Institute of Mental Health–funded study in young people with subthreshold psychotic manifestations. The study is primarily investigating functional outcomes in response to a sequential intervention consisting of support and problem solving, CBCM, and antidepressant medication.

The study was supported by the Stanley Medical Research Institute, the National Health and Medical Research Council Australia Program, and the Colonial Foundation. The study authors and editorialists have received funding and other support from a large number of pharmaceutical companies, which are listed in the original articles.

JAMA Psychiatry. Published online November 23, 2016. Abstract, Editorial

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