Micronutrients as Adjunctive Treatment for Bipolar Disorder

Bipolar disorder is a common neuropsychiatric illness with high rates of morbidity and
mortality. Despite available medications to treat bipolar disorder, recurrence rates are
high. Bipolar disorder is conventionally treated with typical or antipsychotic medications
are well described and include the increased risk of acute kidney injury, cataracts,
decreased cognitive function, increased risk for myocardial infarction and stroke, metabolic
syndrome and type 2 diabetes mellitus, and dyslipidemia. Related to this, mortality rates are
elevated among people with bipolar disorder compared to the general population. Men with the
diagnosis of bipolar disorder live, on average 13.6 years less than the general population,
and for women, 12.1 years less.

This RCT (randomized clinical trial) compares a 36-ingredient Micronutrient supplement and
Fish oil supplement to matched double placebo in patients randomized to receive one or the
other for 52 weeks. One hundred twenty (120) patients are randomized in a 3:2 ratio to
Micronutrient + Fish oil or to placebo, respectively. All patients are stably medicated adult
outpatients with bipolar disorder (type I or type II). Medical supervision is provided with
monthly appointments. At the end of the 52 weeks, all participants will be offered the
opportunity of entering a 52-week open-label extension. The primary hypothesis is that active
supplementation will allow significantly more reduction of conventional medication than
placebo will, without a significant increase in symptoms and with significantly fewer side
effects/adverse events.

The objective of this study is to assess the efficacy of Micronutrient supplement + Fish oil
compared with placebo in stably medicated adults with bipolar disorder I and II, in improving
nutritional status, allowing conventional medication to be effective at lower doses and with
fewer side effects at the end of 52 weeks of therapy as assessed under randomized and fully
blinded conditions. The primary outcome measure is a composite z-score for side effects,
calculated from three separate z-scores that measure medication dosage, illness intensity
(Clinical Global Impression score), and adverse side effects (UKU Side Effect score).
Secondary outcomes include

- Symptom severity using the Positive and Negative Symptom Scale (PANSS)

- Mania symptoms using the Young Mania Rating Scale (YMRS)

- Anxiety symptoms using the Hamilton Anxiety scale (Ham-A)

- Depression symptoms using the Montgomery-Asberg Depression Rating Scale (MADRS)

- Quality of life, patient-reported using My Medical Outcome Profile version 2 (MYMOP-2)

- Nutritional status using the Mini Nutritional Assessment scale (MNA)

- Functionality, patient-reported using the 24-item Behavior and Symptom Identification
Scale (BASIS-24)

- Vital signs (waist circumference, body mass index, blood pressure, heart rate, and
respirations)

Treatment-emergent adverse events are documented at each appointment using the Adverse Event
Log. Participants are screened and their suitability for the trial confirmed at the first
visit. If suitability is confirmed, informed consent is obtained and they enter the
randomized phase. Participants are seen monthly for 12 months, at which time (1) their
medication is optimized (graded reduction in dose by 10% per month, upwards if symptoms are
above the acceptable level and downwards if an acceptable level of symptom relief has been
achieved); (2) symptoms and side effects are recorded; and (3) questionnaires are
administered.

Inclusion Criteria:

Individuals enrolled will be adult outpatients with a diagnosis of bipolar disorder I or
II, receiving care at the Family Medicine Center & Residency Program of Eastern Maine
Medical Center in Bangor, Maine. Participants must be able to complete questionnaires and
examinations and comply with protocols.

Exclusion Criteria:

Participants will be excluded from the study for any of the following reasons:

1. Evidence of untreated or unstable thyroid disease (until it is treated and
stabilized).

2. Known abnormality of mineral metabolism (e.g., Wilson's disease) until stabilized.

3. Unable to speak English

4. Any hypervitaminosis syndrome

5. Acute suicidality (until stabilized).

Participation in the study will not alter the participants' clinical care except that they
will be provided Micronutrients and Fish oil (or placebos for each) and will participate in
a monthly evaluation of the effect of adding these Micronutrients. We will ask them what
other supplements they are taking and will instruct them not to take supplements that
contain any of the same ingredients that they will receive in the study so as to avoid
exceeding the maximum dose allowed.