Neurochemical Effects of Omega-3 Fatty Acids in Adolescents at Risk for Mania

A. Specific Aims: (1) To collect pilot data regarding the efficacy, safety, and
tolerability of omega-3 fatty acid supplementation for the treatment of adolescents with
active depressive symptoms and a high risk for developing mania (i.e. the patient has a
bipolar parent and meet DSM-IV-TR criteria for major depressive disorder). (2) To use
proton magnetic resonance spectroscopy (1H MRS) (i.e. prefrontal neurochemistry) and red
blood cell (RBC) omega-3 fatty acid levels to examine potential mediators of treatment
response to omega-3 fatty acids in adolescents with a high risk for mania.

Inclusion Criterion:

- Ages 10-21 years old.

- At least one biological parent with bipolar I disorder.

- Meets DSM-IV-TR 80 criteria for major depressive disorder (MDD or Depressive Disorder
NOS at screening as determined by the Washington University at St. Louis Kiddie
Schedule for Affective Disorders and Schizophrenia, WASH-U-KSADS;81

- Childhood Depression Rating Scale-Revised Version40,41(CDRS-R) scores greater than or
equal to 28 at screening and baseline.

- Fluent in English.

- Provision of written informed consent/assent as previously described.

- Agrees to use one of the following method of birth control: complete abstinence from
sexual intercourse, barrier (diaphragm or condom), or oral/injectable contraceptive.

Exclusion Criterion:

- Contraindication to an MRI scan (e.g., metal clips, braces or claustrophobia).

- Mood symptoms resulting from acute medical illness or acute intoxication or
withdrawal from drugs or alcohol as determined by careful medical evaluation or rapid
symptom resolution.

- Psychotic symptoms (i.e., hallucinations or delusions).

- Any lifetime history of a manic or hypomanic episode.

- Any lifetime diagnosis of bipolar disorder not otherwise specified (NOS) or
cyclothymia or a current diagnosis of depressive disorder NOS. A current diagnosis of
dysthymia will not be exclusionary, if the adolescent also has a current diagnosis of
MDD.

- A history of a major medical (e.g. diabetes) or neurological illness, laboratory
abnormalities, or a significant episode (> 10 minutes) of loss of consciousness that
could influence the MRS results, as determined by a study physician.

- Any history of alcohol or drug dependence (nicotine dependence is permitted).

- Allergy to shellfish or seafood.

- Mental retardation (IQ<70) as determined by the Wechsler Abbreviated Scale of
Intelligence (WASI), administered by a research coordinator who is a trained
psychometrician.

- A positive serum pregnancy test or lactating.

- A history of intolerance, hypersensitivity or non-response to omega-3 fatty acids.

- Any history of a hematological disorder in themselves or a first-degree relative,
since omega-3 fatty acids may be associated with anti-coagulant effects.

- Concomitant use of medications with anticoagulant effects (e.g. aspirin).

- A lithium or valproate serum level of >0.4 mEq/L and 30 mg/L, respectively at
baseline.

- Use of antipsychotics, other mood stabilizers, stimulants (if opting to discontinue),
or atomoxetine within 72 hours (aripiprazole within two weeks will be exclusionary
because of its long half-life) or antidepressants within 5 days (fluoxetine within
one month will be exclusionary because of its long half-life). Patients treated with
a depot antipsychotic within one dosing interval of baseline will be excluded.
Subjects diagnosed with ADHD and taking a stable dose of stimulants for the previous
month will be permitted to continue if it is determined necessary by subject, primary
caregiver, and treating clinician report in conjunction with the study physician.

- Concomitant use of other psychotropic medications or medications with central nervous
system (CNS) effects within 5 half-lives from baseline MRI scan or prior treatment
with a medication with CNS effects that requires more than 5 days of a screening
period.

- Any psychiatric symptom that requires admission to an inpatient psychiatric hospital,
as determined by a study physician.

- Any initiated psychotherapy within 2 months prior to the screening visit, or plans to
initiate psychotherapy during study participation. Adolescents who present with their
current depressive episode despite longer-term psychotherapy (i.e., >2 months) may be
included. For participants who enter the study on psychotherapy, the type and
frequency of therapy will remain constant during the study.