NAPLS Omega-3 Fatty Acid Versus Placebo Study
Condition: Psychosis
MeSH terms: Psychotic Disorders; Mental Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      The overall goal of the present study is to determine whether Omega-3 Fatty Acids potentially
      prevent onset of psychosis and improve clinical symptoms and functional outcome in youth and
      young adults at elevated clinical risk for schizophrenia and related disorders. The specific
      aims are: (1) To determine whether the rate of progression to psychosis is lower during six
      months of treatment with Omega-3 Fatty Acids compared to six months of treatment with
      placebo, (2) To determine whether Omega-3 Fatty Acids are more efficacious than placebo for
      prodromal symptoms, negative symptoms, and functioning, (3) To assess the safety and
      tolerability of Omega-3 Fatty Acids in this population, and (4) To conduct analyses of
      neuroimaging, neurocognitive, electrophysiological and other ancillary data to explore
      mechanistic explanations for the hypothesized benefits of Omega-3 Fatty Acids on clinical and
      functional outcomes (e.g., increases in white matter integrity and processing speed).
    

Detailed description: 
      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.

      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.
    

Intervention name(s): Omega-3 Long Chain Fatty Acid; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): : 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 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. The dose will be 2 capsules per day.
Other intervention name(s): Fish Oil, Ocean Nutrition
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Prodromal; Schizophrenia; Psychosis; Omega