Light, Ion, and Fluoxetine Efficacy (LIFE) in Depression
Light, Ion, and Fluoxetine Efficacy (LIFE) in Depression
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.
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.
Inclusion Criteria:

 -  Male and female outpatients aged 19-60 years.

 -  Patients will meet DSM-IV criteria for major depressive disorder as determined by the
 mood disorders section of the Mini International Neuropsychiatric Interview (MINI,
 Sheehan et al, 1998).

 -  A score of 20 or greater on the Hamilton Depression Rating Scale (Ham-D), indicating
 at least moderately severe depression.

 -  Competency to give informed consent.

 Exclusion Criteria:

 -  Pregnant women, lactating women and sexually active women of childbearing potential
 who are not using medically accepted means of contraception.

 -  Serious suicidal risks as judged by the clinician and the MINI.

 -  The following DSM-IV diagnoses (to ensure a homogeneous diagnostic group): organic
 mental disorders; substance abuse/dependence, including alcohol, active within the
 last year; schizophrenia, paranoid, or delusional disorders; other psychotic
 disorders; panic disorder or generalized anxiety disorder, if a primary diagnosis;
 obsessive-compulsive disorder or post-traumatic stress disorder; bipolar disorder;
 bulimia nervosa or anorexia nervosa.

 -  Serious illness including cardiac, hepatic, renal, respiratory, endocrinologic,
 neurologic and hematologic disease that is not stabilized, or a past history of
 convulsions.

 -  Any retinal disease or systemic illness with active retinal involvement (e.g.
 diabetes) that precludes the use of bright light.

 -  Patients who have a history of severe allergies and multiple drug adverse reactions.

 -  Regular or current use of other psychotropic drugs, including lithium and tryptophan.

 -  Patients treated with beta blocking drugs.

 -  Hypertensive patients being treated with guanethidine, reserpine, clonidine or
 methyldopa (because of possible mood-altering effects of those drugs).

 -  Use of monoamine oxidase inhibitors within 14 days of Visit 1 (to ensure no drug
 interactions between fluoxetine and MAOIs), or use of heterocyclic antidepressants
 within 7 days of Visit 1 (to ensure adequate washout period of two weeks between
 stopping previous drug and start of treatment at Visit 2).

 -  Previous use of fluoxetine or light therapy.

 -  Treatment resistance in the current episode, as defined by failure (lack of clinically
 significant response) of two or more antidepressants given at therapeutic doses for at
 least 6 weeks.

 -  Patients who start formal psychotherapy (e.g. cognitive-behavioural or interpersonal
 psychotherapy) within 3 months of Visit 1, or who plan to initiate such psychotherapy
 during this study.

 -  Patients involved in any other form of treatment for depression.