NAPLS Omega-3 Fatty Acid Versus Placebo Study

Recruitment of subjects for clinical assessment and testing with dependent measures is
considered for research purposes. Use will be made of existing data and records as the data
obtained from this protocol will be used in combination with all data and records collected
as part of the overall NAPLS study in which subjects are already enrolled. Individuals for
this protocol will be recruited from UCSD's parent NAPLS study.

Experimental Treatment: This will be a 24-week, randomized, double-blind, placebo, fixed
dose-controlled study designed to determine the acceptability and feasibility of Omega-3FA
versus placebo in prodromal subjects assigned to treatments on a 1:1 basis. Omega-3FA will
be administered as oral capsules given twice daily (BID). Ocean Nutrition Canada will
prepare identical-looking Omega-3FA and placebo capsules. The investigators will include 128
prodromal subjects in the 6-month trial. All subjects will receive monthly clinical
assessment. The study design and Omega-3FA formulation are designed to be compatible with
that of another on-going trial conducted by investigators in Australia and Europe (the
Neuropro Study sponsored by the Stanley Foundation), which would enable the data from the
two studies to be combined for analysis on the primary (conversion) and most of the
secondary and tertiary (symptoms, functioning) endpoints.

The proposed study will potentially further the development of novel treatment approach for
the prodrome of psychosis. This research will provide empirical data regarding a lower risk,
broad spectrum treatment, which could have important implications for public health as a
pre-emptive intervention or treatment augmentation because of the potential to effect
functional outcome. It is possible that subjects in the treatment group will show an
improvement in symptoms. Study participants will receive extensive clinical evaluations and
consultation from investigators with knowledge regarding psychosis.

The results of this study will increase the ability to provide alternative treatments with
potentially fewer side effects for the prodrome of psychosis. The potential implication for
primary and tertiary prevention of psychosis from these treatments is immeasurable. Through
the development and utilization of strategies such as those proposed in this research the
investigators could potentially discover the ability to delay the onset of psychosis and
manage treatment more effectively with fewer side effects seen with traditional
antipsychotic medication treatment. The importance of this to public health would be
tremendous.

The use of Omega-3FA in an adolescent and young adult prodromal population is somewhat
novel. Amminger et al 60 utilized a sample of 13 - 25 year old prodromal subjects to
determine the potential benefit of EPA and DHA. Previous studies using Omega-3FA in
adolescent and adult samples of psychotic subjects have produced no significant side
effects. Some subjects reported a fishy aftertaste and mild gastrointestinal difficulties
that dissipated with the discontinuation of Omega-3FA. Therefore the level of risk is
considered minimal. This study offers subjects the possibility of direct benefit from
participation because of the Omega-3FA and placebo treatments. It is also possible that the
concurrent use of Omega-3FA will improve metabolic indices in all subjects. Because
Omega-3FA is not specifically approved by the FDA for use in early psychosis, the
investigators have received a certificate for an Investigational New Drug (IND) for the
current Research Plan.

The sample of 128 prodromal subjects will be recruited from 8 sites over 16 months. UCSD is
expected to recruit 14 of these prodromal subjects. The active treatment phase will be
completed within 6 months, with 12-, 18-, and 24-month follow-ups. Each site will obtain
institutional review board approval of the protocol. The UCLA site directed by Dr. Cannon
and the UCSD site directed by Dr. Cadenhead, coordinate the trial, with responsibility for
acquisition of the Omega-3 and placebo pills, group assignments, and data analysis.

Procedures

During the week prior to randomization and beginning study capsules, patients will undergo
eligibility and baseline examinations. After beginning study capsules, patients will be
scheduled for 6 monthly follow-up visits as well as 12-, 18-, and 24-month follow-ups (Table
1).

Omega-3FA and Placebo: The Omega-3FA compound will be manufactured by Ocean Nutrition Canada
and contain an 2:1 proportion of EPA to DHA in which each capsule includes 370 mg EPA and
200 mg DHA as well as 2 mg/g Tocopherol. The dose will be two capsules per day for a total
of 740 mg of EPA and 400 mg of DHA. The ratio and dose of Omega-3FA were selected based on
previous data from controlled trials that demonstrates the efficacy of EPA in trials with
schizophrenia patients37, 38 and the potential benefit of a low dose of DHA in combination
with EPA per the Amminger study60 in prodromal patients. The placebo is a soybean/corn
blend. Both the Omega-3FA and placebo are colored with carob (so shell is brown) and
flavored with natural lemon-lime, to mask them. Certificates of analysis for the Omega-3FA
and placebo compounds are included in the Appendix. Ongoing testing by independent
laboratories will assure the levels of Omega-3FA in capsules, stability, and absence of any
contaminants, including toxic substances in this product. Stability and toxicology testing
will be provided by Siliker Canada Co. UCLA will receive the compounds and assign coded
numbers to packets before distribution to sites and thereby administer the double blind
design.

Antipsychotics: Prodromal subjects currently on anti-psychotic medication will be excluded
from the study. It is possible that prodromal subjects will develop worsening symptoms and
require such treatments during the course of the trial, which is allowed. All concomitant
treatment will be recorded.

Antidepressants: Prodromal patients currently on anti-depressant medication will be included
in the study; randomization to Omega-3FA vs. placebo will be stratified on anti-depressant
medication status.

Background Diet: Baseline diet characterization will be assessed using a systematic
checklist. The investigators considered using an open-ended diary that requires recording of
all food intake, but it seems unlikely that adolescents with early psychosis symptoms would
comply to a satisfactory degree. The checklist is easy to complete and is more likely to be
accurate than unstructured self-reports. The list includes foods that are rich in Omega-3FA.
It will be given to the family at the first screening visit, and will be collected for the
two consecutive weeks preceding entry into the treatment phase. Intake will be categorized
as low (0-1 serving/wk of Omega-3FA rich diet), intermediate (2-3 servings/wk), or high (4
or more servings/wk). In addition fasting erythrocyte FA composition will be assessed to use
as another means of controlling for background diet at baseline.

Laboratory and Metabolic Measures: After confirming eligibility for the study, a urine
sample will be taken for a drug screen, and a serum pregnancy test on females. Fasting
erythrocyte FA composition will be quantified at baseline, month 3 and month 6 using
capillary gas chromatography. The ratio of Omega-6 to 3FAs will be used to index
pretreatment vs posttreatment FA composition as an objective measure of treatment adherence,
to assess for dietary differences between subjects and assure that subjects on placebo are
not taking Omega-3FA supplementation from an outside source. Thiobarbituric Acid Reactive
Substances (TBARS) will be used for screening and monitoring lipid peroxidation before and
after the treatment trial. In addition, to assess metabolic parameters, baseline measures of
fasting glucose and lipids, weight, abdominal girth and blood pressure will be obtained and
repeated at the end of the trial.

Other Concomitant Medications: Subjects may continue doses of antidepressant, mood
stabilizer, or stimulant medication as prescribed independently of their participation in
this trial. Antipsychotic mediation will not be permitted unless subjects develop worsening
symptoms and require antipsychotic medication during the course of the trial. All
concomitant treatment will be recorded.

Concomitant Psychotherapy: During the 6-month active treatment phase, all subjects will be
receive up to 6 sessions of supportive case management, as needed, as part of their
evaluations by psychological staff. Staff members will provide support and address the young
person's efforts to cope with symptoms and functional deficits. In addition, subjects will
be permitted to participate in any outside of study supportive psychotherapy, with all
concomitant psychological treatments recorded.

Study Management: Prior to study launch, study investigators and other key personnel will
participate in several conference calls to provide training on study procedures, including
recruitment strategies, inclusion and exclusion criteria, use of rating scales, and data
management procedures.

After study launch, the co-PIs at the UCLA and UCSD sites will chair conference calls every
two weeks attended by each site PI and study coordinator. Reports on enrollment and data
completeness will be discussed regularly, along with issues brought up by sites.

Data Management: UCLA will provide the central data management site for the proposed study,
and the University of Calgary site (Dr. Addington) will be responsible for overall NAPLS
data management. This will be done through a centralized Oracle database with web based data
input that will facilitate study coordination, data checks and early identification of
faulty procedures and data errors. The database is secure, robust and easy for clinical
investigators and staff to learn and use. Security access can be limited to site level with
a range of access for different levels of personnel. Data entry will be of the highest
standards such that each data element/field is defined with ranges, allowed values and size.

Post-treatment Biomarkers Assessment

Patients enrolled in this trial will be participants in the parent study "Predictors and
Mechanisms of Conversion to Psychosis." In the context of that study, participants are
assessed with MRI/DTI, electrophysiology (including PPI), neuropsychological testing at
baseline and 12- and 24-month follow-ups. Given that participants in the Omega-3FA study
will complete the active treatment phase at 6 months, it is desirable to add an additional
biomarkers assessment point for those subjects at the 6-month (end of treatment) follow-up.

Assessments

Sources of material will come primarily from the participant, in the form of the results of
questionnaires, clinical interviews, physical exam, and blood draws. All participants will
undergo a series of clinical, functional, neurocognitive, neuroimaging and
electrophysiological assessments, which are part of the overall NAPLS study, before and
after the 6 months of Omega-3FA versus placebo. Therefore data collected as part of the
parent study will be assessed for changes that may be attributable to these treatment
trials. Biological specimens (blood) will be collected at baseline, 3 months and 6 months of
the Omega-3FA trial to help evaluate the level of Omega-3FA in the diet and metabolic
indices as well (urine) to evaluate substance use at time of testing.

For minors, a parent/legal guardian may provide additional information useful for clinical
or historical data. Written and oral consent will be obtained from participants, or their
legal guardian for minor participants. Assent will be obtained from minors. Only study
personnel directly associated with the research will have access to individually
identifiable information.

Inclusion Criteria:

- Subjects will be included if they are treatment-seeking patients between the ages of
12 and 30 who meet diagnostic criteria for a possible prodromal syndrome and are part
of the ongoing NAPLS study.

Exclusion Criteria:

- use of antipsychotic medication in the previous month.

- concomitant medical or neurological illness.

- history of significant head injury.

- alcohol or drug abuse (excluding nicotine) in the past month or dependence in the
past three months.

- screening full scale estimated IQ < 80.

- active suicidal or homicidal ideation.

- pregnancy or lactation.

- allergies to seafood or seafood related products or no history of seafood consumption