Light, Ion, and Fluoxetine Efficacy (LIFE) in Depression
Condition: Major Depressive Disorder (MDD)
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 3

Summary: 
      This study will investigate the additional benefits of light and ion therapy as added
      treatments to an antidepressant (fluoxetine) in subjects with major depressive disorder
      (MDD), versus treatment with fluoxetine alone. Outcomes will include depressive symptom
      rating scales and measures of quality of life, work absence and productivity, and use of
      health care services. The primary hypotheses are that, in patients with nonseasonal major
      depressive disorder (MDD) of at least moderate severity: 1) bright light therapy or negative
      ion therapy will be superior to a placebo condition in reducing symptoms of depression, and
      2) the combination of fluoxetine and either bright light or negative ion therapy is more
      effective than either monotherapy condition.
    

Detailed description: 
      Rationale

      Many effective treatments exist for depression, including psychotherapies and antidepressant
      medications. However, antidepressants are not always effective, and they can produce
      significant side effects and pose a risk of overdose. Medication can also be expensive,
      thereby limiting accessibility. Furthermore, many people with MDD prefer to use
      non-pharmacological treatments. Some studies have found that combination antidepressant and
      psychotherapy is more effective than either monotherapy in people with chronic forms of MDD.
      However, evidence-based psychotherapies such as cognitive-behavioural therapy are not widely
      available within the Canadian health care system.

      For these reasons, there is great interest in finding alternative treatments to
      antidepressants and psychotherapy. Bright light therapy, which is well established as an
      effective treatment for seasonal affective disorder (SAD), has many attributes that make it
      highly attractive to use for nonseasonal MDD: it is a safe, well-tolerated, inexpensive, easy
      to use, non-pharmacological treatment that can be used as monotherapy or combined with
      medications without the worry of drug-drug interactions. The "gold standard" method for
      applying light therapy is via a 10,000 lux white fluorescent light box for 30 minutes a day,
      usually in the early morning upon arising from bed. The mechanism of action of light therapy
      is still unknown, but major hypotheses involve resynchronizing circadian rhythms and/or
      restoring neurotransmitter dysfunction. Bright light has predictable phase-shifting effects
      on circadian rhythms in humans, but studies of light therapy have not consistently
      demonstrated correlations of phase shift with antidepressant response. Although most of these
      studies have been done in patients with SAD, there is considerable evidence that nonseasonal
      MDD is also associated with disturbances in circadian rhythms. Other studies have shown that
      rapidly depleting serotonin and catecholamines can reverse the antidepressant effects of
      light therapy in SAD, thereby demonstrating monoaminergic effects of bright light similar to
      those seen with antidepressants. These chronobiologic and monoaminergic effects of bright
      light provide a rationale for the use of light therapy in nonseasonal MDD. As well, initial
      studies have shown that negative ion generators may be an effective treatment for
      neurovegetative symptoms of SAD, specifically oversleeping, overeating, and fatigability.
      However, relatively few studies have been conducted of light and ion therapy in nonseasonal
      MDD. Several systematic reviews of light and ion therapy for nonseasonal MDD have shown some
      support for efficacy, but these are based on a limited number of small-sample, poorly
      controlled RCTs.

      Research Method

      This study is an 8-week, multi-centre, double-blind (subject and rater), randomized,
      parallel-design trial to assess the efficacy of light and ion therapy when combined with
      fluoxetine in the treatment of subjects with MDD, compared to treatment with fluoxetine
      alone. A total of 216 depressed patients meeting entry criteria will be enrolled over a
      three-year period.

      Eligible patients will be randomized to one of four treatment conditions for the entire
      treatment period (8 weeks):

        1. light treatment using a fluorescent light box (30 minutes daily) plus a placebo pill
           every day; or

        2. negative ion generator (30 minutes daily) plus 20 mg of fluoxetine per day; or

        3. negative ion generator (30 minutes daily) plus placebo pill every day; or

        4. light treatment using a fluorescent light box (30 minutes daily) plus 20 mg of
           fluoxetine per day.

      Half of all devices (light boxes and negative ions) will be deactivated to test placebo
      conditions.

      Outcomes (HAM-D) will be primarily assessed over the telephone by raters blind to treatment
      assignment. Other outcome measures will be assessed by patient-rated questionnaires
      administered over the Internet using a secure web site, and by ratings from the treating
      physician (CGI and Health Economics Assessment).

      Statistical Analysis All randomized subjects who have at least one follow-up visit will be
      included in the analysis based on intent-to-treat. Ineligible subjects who are
      inappropriately randomized will be excluded from the analysis. Missing data will be imputed
      using last observation carried forward (LOCF). For the analyses the treatment variables will
      remain coded and the analysts and investigators will remain blinded to variable identity
      during analysis and interpretation.

      The pre-specified primary efficacy endpoint is the adjusted mean change from baseline to
      endpoint (8 weeks) in the HAM-D score using LOCF. All comparisons will be analyzed using
      ANCOVA adjusting for baseline value and centre. The secondary outcomes will also be analyzed
      using a similar analysis, when appropriate. Post-hoc analyses will also examine observed case
      data. Categorical data (such as proportions of the sample with adverse events) will be
      analyzed using chi-square tests or Fisher's test where cell sizes warrant.
    

Intervention name(s): Light treatment; Negative ion therapy; Placebo; Fluoxetine
Intervention type(s): Procedure; Procedure; Drug; Drug
Intervention description(s): Light therapy: from a 10,000 lux fluorescent white light box, for 30 minutes per day upon waking in the morning, for 8 weeks.; Negative ion therapy: from a negative ion generator with an output of 200 trillion ions per second per cubic centimeter, for 30 minutes per day upon waking in the morning, for 8 weeks; Placebo Pill: one oral tablet each day, for 8 weeks.; Fluoxetine: 20 mg oral tablet each day, for 8 weeks
Intervention MeSH terms: Fluoxetine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depression; rating scales; RCT; combination treatment; light therapy; negative ion therapy; fluoxetine; antidepressants