Study design

A randomized, double-blind, placebo-controlled trial consisting of: (1) a 12-week intervention period with 1.2 g per day omega-3 PUFAs or placebo; (2) a 40-week period during which all participants received state-of-the-art clinical care; and (3) a longer-term follow-up assessment. The study was approved by the Medical University of Vienna ethics committee, and written informed consent was obtained from all participants (parental or guardian consent was obtained for those aged <18 years). Longer-term follow-up data were collected between March 2012 and December 2013. All study participants and raters were blind to group allocation (that is, omega-3 PUFAs; placebo).

Longer-term follow-up procedure

The study was conducted at the Department of Child and Adolescent Psychiatry, Medical University Vienna, Austria. Informed consent for the longer-term follow-up was gained at time of the baseline assessment. We maximized the follow-up rate using a six-step sequential algorithm for follow-up: (1) research files; (2) psychiatric medical records; (3) a Vienna-wide electronic register of health service utilization; (4) telephone directory; (5) national register of residents; and (6) National Death Index. The research files contain the past assessments and contact details, including those of next of kin. The electronic register of health service utilization was used to obtain information regarding whether participants had been registered with the public mental health system since the last follow-up. Resident registration is compulsory in Austria. The register of residents is a government database containing information on the current residence of persons. The telephone directory was searched for the names of participants and any family members whose names were known to obtain contact information. The National Death Index was used to check whether participants were deceased. Once a possible location for an individual had been determined, he or she was sent a standard letter explaining the purpose of the project and advising that a member of the research team would be in contact. Once an individual was contacted, he or she was invited to participate in a follow-up interview.

Patient eligibility criteria and exclusion criteria

Individuals were eligible for participation if they were aged 13–25 years and met criteria for at least one of three operationally defined groups of specific state and/or trait risk factors for psychosis. The three groups were as follows: (1) attenuated positive psychotic symptoms; (2) brief, limited intermittent psychotic symptoms (transient psychosis); and (3) trait plus state risk factors (that is, genetic risk plus a decrease in functioning). The rationale and validation for these ultrahigh risk groups has been previously described12,27,28. Following Morrison et al.17, we used the PANSS13 to operationalize the first two groups by applying the following cutoff scores: attenuated psychotic symptoms were defined by the presence of symptom scores of 3 on the delusions scale, 2–3 on the hallucinations scale, 3–4 on suspiciousness or 3–4 on the conceptual disorganization scale (frequency of symptoms several times per week for a period of at least a week and not longer than 5 years, and have occurred within the last year); transient psychosis was defined by the presence of symptom scores of 4 or more on the hallucinations scale, 4 or more on the delusions scale, or 5 or more on the conceptual disorganization scale (symptoms not sustained beyond a week, resolve without antipsychotic medication and have occurred within the last year). The third group, comprising trait plus state risk factors, was defined as having a schizotypal personality disorder (as defined by DSM-IV) or a first-degree relative with a DSM-IV psychotic disorder, and a significant decrease in functioning resulting in a decrease of 30% on the GAF15 from the premorbid level, maintained for at least a month and not longer than 5 years. The decrease in functioning needed to have occurred within the previous year.

Individuals were excluded from the study if they had the following: (1) a history of a previous psychotic episode (treated or untreated) or substance-induced psychotic disorder at index presentation; (2) acute suicidal or aggressive behaviour (PANSS hostility or suicidality=7); (3) drug abuse that contributed decisively to the presentation of the index episode (dependency on morphine, cocaine, amphetamine, but not cannabis); (4) alcohol abuse if considered as a major problem; (5) epilepsy; (6) IQ<70; (7) structural changes in magnetic resonance imaging or computed tomography scan (for example, tumours), except for enlargement of ventricles or sulci; (8) previous treatment with an antipsychotic or mood stabilizing agent (more than three daily doses); (9) laboratory values >10% outside the normal range for transaminases, CRP or bleeding parameters; (10) organic brain syndrome; (11) had taken or were taking omega-3 supplements currently or within 8 weeks of being included in the trial; and (12) another severe, intercurrent illness that in the opinion of the investigator may put them at risk or influence the results of the trial, or affect ability to take part in the trial. More information on trial design, interventions, randomization, blinding and study measures is provided by Amminger et al.11.

Outcome measures

The primary efficacy measure for the treatment comparison was the rate of conversion to psychosis, which was operationally defined based on criteria by Yung et al.12, using cutoff points on the PANSS) (4 or more on hallucinations, 4 or more on delusions and 5 or more on conceptual disorganization), the frequency of symptoms (at least several times a week), and their duration (more than 1 week). The exit criteria marked the threshold (linked to positive symptoms) at which treatment with antipsychotic medication is usually initiated18. Secondary efficacy measures included the PANSS13, the MADRS14 and the GAF15. The SCID-I/P16 was used to ascertain psychiatric diagnoses at baseline, 12-month, and longer-term follow-up. The SCID ratings at 12-month and longer-term follow-up were supplemented by additional sources, including a medical records review and an informant interview, usually conducted with a parent or caregiver.

Inter-rater reliability

Raters were experienced clinicians who were thoroughly trained in the administration of outcome measures before the beginning of the study. Inter-rater reliability estimates for PANSS subscales, MADRS and GAF were excellent (all intraclass correlation coefficients ⩾0.92)11. To maintain reliability between raters, videotaped interviews were used approximately every 3 months across the initial 12 months of the study and before the longer-term follow-up was commenced.

Data analysis

Analyses were performed on an intention-to-treat basis. Kaplan–Meier survival analysis assessed differences in time to transition to psychosis between the treatment arms at longer-term follow-up using the log-rank test. A secondary sensitivity analysis was performed under the assumption that all participants who were lost to follow-up prior to the longer-term follow-up assessment had converted to psychosis. For secondary outcome measures, analyses were carried using the mixed model repeated-measures analysis of variance. The within-groups factor was measurement occasion, and medication group served as the between-groups factor. A Toeplitz co-variance structure was used to model relations between observations on different occasions. A series of planned comparisons contrasted change from baseline to the 12-week, 6-month, 12-month and longer-term follow-up assessments between omega-3 and placebo. Mixed model repeated-measures analysis of variance differs from traditional repeated-measures analysis of variance in that all available data are included in the model and the associations between the different times are also modelled. Analyses were undertaken using the MIXED procedure in SPSS, version 21. In accordance with our original analysis, the score at the time of transition to psychosis (that is, the time when a participant exited the trial and commenced antipsychotic medication) was used in the analysis for those individuals who converted to psychosis. A transition score has been prospectively assigned to individuals in the original study who developed psychosis before the 12-month follow-up11. In those individuals who made a transition to psychosis after the 12-month follow-up, transition scores were estimated retrospectively at longer-term follow-up based on interview and/or hospital record information. For comparisons of categorical variables, we calculated Pearson’s χ2-tests. A significance level of 0.05 was used for all statistical tests, and all tests were two tailed.