Prevention of Mood Disorders by Folic Acid Supplementation
Condition: Depression; Bipolar Disorder
MeSH terms: Depression; Bipolar Disorder; Mood Disorders
Study type: Interventional

Summary: 
      The purpose of this study is to determine whether daily folic acid supplements can prevent
      new episodes of mood disorder in young people (aged 14-24 years) of biological parents with
      current or past history of depression or bipolar disorder.
    

Detailed description: 
      Bipolar disorder and recurrent major depression are life-long disabling illnesses that often
      first become clinically apparent in the late teenage years or early twenties. People who
      develop clinical mood disorders characteristically have milder, short-lived symptoms of mood
      disturbance prior to the onset of clinical illness. These sub-clinical disturbances represent
      a risk factor for the subsequent development of clinical disorders (Angst 2000; Aalto-Setala,
      2002). A number of physiological abnormalities associated with depression persist after
      symptom resolution, suggesting that depression may cause a kind of biological "scarring" of
      the brain that can predispose to further episodes of illness.

      Nutritional supplements are a feasible intervention for primary prevention because they are
      likely to be acceptable and intuitively would seem to have a greater chance of being
      effective at a preventative stage, rather than later when disease progression has occurred.

      Folate and mood disturbance

      Low plasma and red cell folate have long been associated with clinical depressive disorders
      and treatment with folic acid (500mcg daily) has been shown to improve the therapeutic effect
      of fluoxetine in depressed patients (see Coppen and Bailey, 2000). A growing number of
      epidemiological studies also suggest links between low folate status, increased homocysteine
      and depressive symptomatology in the general population (Tiemeier et al, 2002; Bjelland et
      al, 2003; Morris et al, 2003).

      Objectives

      Primary

      • To determine whether folic acid supplementation can prevent new episodes of mood disorder
      in teenage children of parents with recurrent depression or bipolar disorder

      Secondary

        -  To determine whether folic acid supplementation can improve depression scores on the
           Mood and Feeling Questionnaire in teenage children of parents with recurrent depression
           or bipolar disorder

        -  To determine whether folic acid supplementation can improve scores on the Altman Mania
           Rating Scale in teenage children of parents with recurrent depression or bipolar
           disorder

        -  To determine whether there is a correlation between genotypes for folate enzymes and
           response to folate

      Endpoints

      Primary

      • Occurrence of an episode of Axis 1 mood disorder on DSM-IV as determined by the Structured
      Clinical Interview for DSM-IV (SCID)

      Secondary

        -  Change in Score on The Mood and Feeling Questionnaire

        -  Change in score on the Altman Mania Rating Scale

        -  Correlation between genotypes for folate enzymes and response to folate

      Study design

      This will be a randomized, concealed allocation, placebo-controlled study with masking of
      participants and investigators. Participants will initially enter a 4 week run-in phase
      during which they take folic acid (2.5mg). If consent and compliance are maintained during
      the active run-in, participants with then be randomised to one of two treatments in a
      parallel group design (a) Folic acid (2.5mg daily) or (b) identical placebo liquid. A
      web-based algorithm will be used which will be accessed by researchers either online or by
      phone call to the study office. Access to the randomisation code will be limited to the trial
      programmer with temporary access given to another member of the trial team during her
      absence. The treatment period will be thirty six months.

      PRE-EMPT will continue screening until there are 200 teenagers in the randomised phase, male
      and female (14-24 years of age) who have a biological parent with a life-time history of
      recurrent major depression, bipolar I or bipolar II disorder. Family history will be assessed
      using proband questions. Subjects will be excluded if they have any current or past DSM-IV
      Axis I disorder. This will be assessed using the Structured Clinical Interview for DSM-IV
      (SCID). Current or past sub-syndromal mood and anxiety disorder will not be a reason for
      exclusion but will be assessed and used in the minimization process.We will also exclude
      subjects with a significant on-going medical condition, particularly epilepsy or those who
      are already using folate supplements and who are unwilling to give them up for the duration
      of the study. All subjects will give informed written consent to the study and a parent or
      guardian will also give written consent where subjects are under 16 years of age.
      Minimization will be carried out for age, gender, family history and the presence of
      sub-syndromal mood disturbance to ensure balanced treatment allocation.

      Ratings and follow-up On entry to the study subjects will complete ten self-rating
      instruments, the Mood and Feeling Questionnaire (MFQ), a 32-item scale designed to detect and
      monitor adolescent depression in the community (Cooper and Goodyer, 1993; Wood et al, 1995).
      Subjects will also complete the Altman Mania Rating Scale, a 5-item scale designed to mania
      (Altman et al, 1997), the Insomnia Severity Index (ISI), a 5-item scale designed to detect
      the severity of insomnia (Morin 1993), and the Hospital Anxiety and Depression Scale (HADS) a
      14 item scale to determine anxiety and depression (Zigmond and Snaith 1983). Subsequently
      subjects will complete the MFQ, Altman, ISI and HADS monthly. We will have available both
      web-based assessments and written forms, whichever the participant prefers. The other rating
      scales to be completed on entry are the Cambridge Life Events Rating Scale (CLE), Eysenck
      Personality Questionnaire (EPQ), Response Styles Questionnaire (RSQ), Parental Bonding
      Inventory (PBI), Children's Attributional Style Questionnaire (CAS). and the
      Morningness-Eveningness Questionnaire (MEQ).

      At six monthly intervals subjects will be re-interviewed with the SCID to assess whether they
      have met criteria for any DSM-IV Axis I disorder in the preceding six months. The CLE and CAS
      will also be repeated at six monthly intervals.

      Prior to entry to the investigation we ask subjects to provide a blood sample for the
      following:

        1. Full blood count, Red cell folate, B12, homocysteine levels

        2. DNA sample for polymorphisms of the proteins involved in folate metabolism and related
           neurotransmitters.

      These measures (apart from the DNA analysis) will be repeated annually.

      Prior to entry we also wish to assess waking salivary cortisol. In a separate study we have
      found that healthy young people with a parent who has a history of mood disorder (ie the same
      participant population that we are recruiting for this study) have elevated waking levels of
      salivary cortisol relative to controls.The measurement of waking salivary cortisol is a
      simple non-invasive test which may represent a marker of vulnerability to depression. If this
      is the case it might be altered by folate treatment which we are using in the present study
      to decrease the risk of depression.

      We therefore propose to ask subjects to take a sample of waking salivary cortisol before they
      begin folate/placebo treatment and again after about six months in the study. In this way we
      will be able to assess the effect of folate/placebo treatment on waking salivary cortisol.
      The eventual aim will be assess whether relative to placebo folic acid treatment lowers
      waking salivary cortisol and whether this is associated with decreased risk of depression.

      From the point of view of storage and custody the saliva samples will be treated exactly as
      the blood samples taken for folate estimation.
    

Intervention name(s): Folic Acid; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Folic acid oral solution 2.5mg/5ml daily for up to 3 years; Matching placebo for folic acid oral solution (2.5mg/5ml)
Other intervention name(s): Lexpec PL 0427/0034
Intervention MeSH terms: Folic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Folic Acid; Prevention; Depression; Bipolar Disorder; Teenagers