Essential Fatty Acids for Major Depression
Condition: Major Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

Summary: 
      This is a research study to determine whether omega-3 fatty acid supplementation, when taken
      with the antidepressant medication escitalopram (Lexapro), helps to improve depressive
      symptoms in individuals who have major depressive disorder (MDD).

      Omega-3 fatty acids are found in foods including walnuts, some fruits and vegetables, and
      coldwater fish such as herring, mackerel, sturgeon, and anchovies.
    

Detailed description: 
      Primary aims

      Aim 1: To determine whether measures of essential fatty acid (EFA) membrane composition
      predict symptom improvement during selective serotonin reuptake inhibitor (SSRI) treatment of
      major depressive disorder.

      Aim 2: To determine whether augmentation with the EFA eicosapentaenoic acid (EPA) is likely
      to benefit patients who have had an inadequate improvement following four weeks of SSRI
      monotherapy.

      Aim 3: To determine the degree to which improvement following omega-3 supplementation in SSRI
      partial responders reflects changes in the erythrocyte concentrations of EPA and DHA and in
      the ratio of EPA to arachidonic acid (AA) erythrocyte concentrations.

      Secondary Aim:

      To determine whether relationships between changes in tissue EFA concentrations and changes
      in depressive symptoms following omega-3 supplementation are mediated by changes in cytokine
      activity.

      Primary Hypotheses:

      Hypothesis 1: After four weeks of treatment with the SSRI escitalopram Montgomery-Asberg
      Depression Rating Scale (MADRS) scores will correlate positively with baseline RBC
      concentrations of EPA and DHA and negatively with baseline erythrocyte ratios of AA to EPA.

      Hypothesis 2: Among patients who continue to meet criteria for MDD after four weeks of
      treatment, both those randomized to .7 grams and those randomized to 1.5 grams daily of EPA
      supplementation will show a greater mean improvement in MADRS scores after an additional six
      weeks than will those assigned to placebo supplementation.

      Hypothesis 3: After patients who have had inadequate antidepressant responses to SSRI
      treatment complete six weeks of augmentation with placebo, or with .7 grams or 1.5 grams per
      day of EPA, a relationships will exist between final MADRS scores and both the final RBC
      concentrations of DHA and EPA and the final RBC ratio of AA to EPA. These relationships will
      resemble those between baseline RBC concentrations and subsequent responses to escitalopram
      and will suggest therapeutic ranges for these concentrations.

      Secondary Hypothesis:

      Among patients with erythrocyte EPA concentrations less than 0.82% at the beginning of the
      augmentation trial, the association between subsequent changes in depressive symptoms and EPA
      tissue concentrations will be markedly reduced by the introduction of changes in IL-1 beta,
      IL-10 and PGE2 into the model.

      Study Design:

      Phase one is a four-week open trial and is designed to test specific response predictors. A
      subset of subjects who complete phase one will enter phase two, a six-week, double-blind,
      placebo-controlled trial designed to show whether eicosapentaenoic acid (EPA) is an effective
      augmentation agent in patients who have had an inadequate antidepressant response.

      A pilot of thirty (30) subjects, aged 18-55 years, with current major depressive disorder who
      have taken not regularly taken antidepressants in the previous month. Cognitively impaired
      subjects will not be included.

      This is a pilot study designed to demonstrate the feasibility for an NIMH application. It is
      not currently powered to statistically test the listed hypotheses.

      Study outcomes/endpoints:

      The primary outcomes for both phases will be the final MADRS score.

      Study Procedures:

      Subjects will be recruited through advertisement and through the University of Iowa Hospitals
      and Clinics (UIHC) adult clinic. Advertisements will also be placed in the newspapers of
      cities within a 100-mile radius of UIHC.

      Screening procedures:

      The study's research associate will screen calls, contact respondents, and administer the
      screening to determine eligibility. Those who appear to satisfy entry criteria will be given
      appointments to meet with the PI and Co-PI. If the in-person evaluation confirms the
      subject's eligibility, he or she will be given a consent form and be invited to ask any
      remaining questions he or she might have. The protocol could begin at that visit.

      Study Intervention:

      Active study agents: Escitalopram and eicosupentaenoic acid (EPA). A variety of
      antidepressants are available for the treatment of Major Depressive Disorder (MDD). A number
      of psychotherapeutic approaches also have demonstrated effectiveness. Potential subjects
      could receive both escitalopram and EPA without participating in the study.

      Placebo study agents: Placebo capsules will match the EPA capsules.

      Storage:

      Drug will be locked and maintained in the medical education building. Data forms and
      computerized data will be stored in the University of Iowa Medical Education Building.
      Offices and cabinets will be locked, computer files will be password protected. The lab of
      Arthur Spector, M.D. will analyze the blood samples.

      Administration:

      In phase one, subject will be given a 4 week supply of 10 mg escitalopram (Lexapro) and
      instructed to take one pill a day for 4 weeks.

      If eligible for phase 2 of the study, subject will continue to take 10 mg of escitalopram but
      will also be randomly assigned to take, in addition, either 0.7 grams or 1.5grams of the EPA
      or a placebo.

      ** If depression symptoms have improved by greater than 50% at the end of week 4, subject
      will be given a 1 month supply of escitalopram and will be assisted in obtaining psychiatric
      care in their area.

      If depression symptoms have not improved by greater than 50% at the end of week 4 subject
      will be invited to participate in Phase 2 of the study.

      The protocol will begin with the administration of a structured diagnostic interview, the
      Structured Clinical Interview for DSM IV Diagnosis (SCID), and two depression rating scales,
      the Montgomery Asburg Depression Rating Scale (MADRS) and the Hamilton Rating Scale (HRS).
      Two tubes of blood will be drawn, one for erythrocyte EFA concentration determination and the
      other for quantification of inflammatory markers (c-reactive protein). Subjects will then be
      supplied with a one-month supply of escitalopram (Lexapro) with instructions to take one 10mg
      capsule each morning. Return visits at two weeks and four weeks will be scheduled and
      subjects will be instructed to return with any remaining medication.

      Subjects will be contacted at weekly intervals. During a brief telephone conversation he or
      she will ask whether the subject has any questions or has experienced any troublesome side
      effects.

      Those who meet the criteria for inadequate escitalopram response described above will be
      invited to participate in a six-week trial of supplemental omega-3. Subjects will continue
      taking escitalopram at the previous dose of 10mg daily but will be randomly assigned to take,
      in addition, either 0.7 grams or 1.5 grams of the eicosapentaenoic acid (EPA) or a placebo.

      Visits for phase 2 will be scheduled at weeks 6, 8, and 10. At week 4 and 10 blood samples
      for erythrocyte EFA concentrations and cytokine determinations will be drawn. MADRS will be
      rated on these visits.
    

Intervention name(s): Eicosapentaenoic acid (EPA) 0.7 grams/day or 1.5 grams/day; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Placebo and Omega 3 capsules. All participants receive 4 capsules with either 0, 2, or 4 capsules containing omega 3.; 4 capsules of placebo each day
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment