Non-seasonal Major Depressive Disorder: Bright Light Therapy and/or Fluoxetine
By Ellen Feldman, MD
Altru Health System, Grand Forks, ND
Dr. Feldman reports no financial relationships relevant to this field of study.
SUMMARY POINTS
- In this study, 122 adult patients were randomized to one of the following treatments: 1) light therapy at 10,000 lux, 30 minutes daily, and placebo pill; 2) sham light and fluoxetine 20 mg daily; 3) combination of light therapy at 10,000 lux, 30 minutes daily, and fluoxetine 20 mg daily; or 4) sham light and placebo pill.
- Montgomery-Asberg Depression Rating Scale (MADRS) was used to measure response and remission periodically during the 8 weeks of this study; other rating scales were used to measure secondary outcomes.
- Combination therapy showed the most statistically significant improvement when compared with sham-placebo, light therapy plus placebo showed some benefits, and fluoxetine plus sham light was not statistically different from placebo.
SOURCE: Lam RW, et al. Efficacy of bright light treatment, fluoxetine, and the combination in patients with nonseasonal major depressive disorder. JAMA Psychiatry 2016;73:56-63. doi:10.1001/jamapsychiatry.2015.2235.
SYNOPSIS: In this four-pronged study comparing the effect of bright light treatment, fluoxetine, a combination of these two interventions, and placebo in patients with major depressive disorder, the combination treatment appears the most consistently effective.
Judicious exposure to full-spectrum light is an accepted and effective treatment for seasonal affective disorder.1 There has been some thought that light could potentially benefit patients with major depressive disorder (MDD) as well, given the disruption in circadian rhythm associated with depression and the effect of light exposure in restoring normal rhythms. However, until now studies have yielded conflicting evidence for this hypothesis.2 The primary objective of this multicenter Canadian investigation was to test a dual hypothesis in adult patients with non-seasonal MDD:
- Light treatment is more effective than placebo.
- In combination, light treatment and antidepressant medication is more effective than either treatment alone or placebo.
One of the major downfalls of previous studies looking at light treatment in non-seasonal depression has been the lack of a sham condition (light placebo) and the relatively short length of the studies (too short to allow evaluation of response to medication.) This study attempted to address both of these issues by creating a sham-placebo arm using a negative ion generator and continuing the study for a full 8 weeks. Negative ion generators are electrical devices that emit streams of negatively charged ions. In this study, the devices were deactivated and modified to emit a humming sound. Participants were given instructions identical to the group with active light boxes. These conditions were designed to provide credibility; expectation ratings were measured in all groups and found to be quite similar.
The original intent of this study was to enroll 216 patients across six psychiatric clinics in different locations. Lack of participation at several of the centers resulted in a three-clinic study involving 122 patients, all of whom met DSM-IV-TR criteria for MDD.
Pertinent exclusions included comorbid unstable medical disorders, most retinal disorders, and psychiatric disorders (i.e., bipolar, psychosis, or current substance abuse; a seasonal pattern to symptoms; pregnancy; serious risk of suicide; a history of use of light therapy or fluoxetine; and concurrent treatments for depression such as antidepressant use or psychotherapy). In addition, patients whose symptoms spontaneously remitted during an initial week-long period without active treatment were excluded. The 122 patients were randomized to one of the following four treatment arms of the study.
- Active light box — 32 patients. Fluorescent light box (10,000 lux) and placebo pill: directions were to be exposed to light box 30 minutes each morning.
- Active fluoxetine — 31 patients. Sham light box (deactivated negative ion generator with audible hum) and fluoxetine 20 mg: directions identical to treatment 1.
- Sham-placebo — 30 patients. Sham light box (as above) and placebo capsule: directions identical to treatment 1.
- Combination — 29 patients. Fluorescent light box (10,000 lux) and fluoxetine 20 mg: directions identical to treatment 1.
The Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess response and remission. This scale was chosen due to good inter-rater reliability on telephone evaluations. In this study, telephone evaluations were conducted during weeks 1, 2, 4, 6, and 8. The MADRS is a 10-item scale scored from 0- 60 and is designed to be sensitive to changes resulting from antidepressant use.3 Remission was defined as a MADRS scale ≤ 10; response was defined as a reduction in MADRS score of at least 50% from baseline. The mean MADRS score at week 0 and mean decrease in MADRS score at the end of 8 weeks for each arm are depicted in Table 1. Table 2 lists the remission and response rates for each arm and the relevant P values.
Table 1: MADRS changes week 0 to week 8 and corresponding P values |
|||
|
Mean MADRS week 0 |
Mean decrease MADRS week 8 |
P values vs sham-placebo |
|
|
Light box-placebo |
27.0 |
13.4 |
P = 0.006 |
|
Sham-fluoxetine |
26.6 |
8.8 |
P = 0.32 |
|
Sham-placebo |
25.8 |
6.5 |
|
|
Combination light box and fluoxetine |
26.9 |
16.9 |
P < 0.001 |
Table 2: MADRS Response (week 8 MADRS reduced by at least 50 %) and Remission (week 8 MADRS < 10) for each group |
||||
|
Light-placebo n = 32 |
Sham-fluoxetine n = 31 |
Sham-placebo n = 30 |
Combination n = 29 |
|
|
Percent remission (MADRS ≤ 10 by week 8 ) |
43.8 *P = 0.27 vs sham-placebo |
19.4 *P = 0.31 vs sham-placebo |
30 |
58.6 *P = 0.02 vs sham-placebo |
|
Percent response (MADRS reduced at least 50% by week 8) |
50 *P = 0.17 vs sham-placebo |
29 *P = 0.69 vs sham-placebo |
33.3 |
75.9 *P = 0.005 vs sham-placebo |
Treatment Emergent Side Effects (TEAE). Each arm of this study had more than 50% of the subjects self-reporting a TEAE. Most were transient symptoms. The dropout rates due to TEAE were similar in each group, leading the authors to conclude that for the most part each intervention was well tolerated.
COMMENTARY
There is no point treating a depressed person as though she were just feeling sad, saying, “There now, hang on, you’ll get over it.” Sadness is more or less like a head cold — with patience, it passes. Depression is like cancer.
— Barbara Kingsolver, The Bean Trees
Depression affects an estimated 350 million people worldwide.4 Untreated depression waxes and wanes but most commonly progresses insidiously with disability, worsening of chronic medical conditions, and even suicide as possible outcomes.5 Antidepressant medication is a conventional treatment for depression.6 Poor compliance with long-term use of medications (current recommendations are a 1- to 2-year course of treatment) and patient preference for alternative and adjunct treatment drive the search for less intrusive, more effective, and well-tolerated interventions.
Treatment of seasonal depression with full spectrum light at 30 minutes daily is an accepted intervention for this specific category of affective illness.1 Using this same intervention for non-seasonal MDD is theoretically interesting but not yet well accepted or tested. The authors claim that this study represents the first well-controlled and appropriately designed study investigating light monotherapy and combination therapy (light and antidepressant medication) in the treatment of non-seasonal MDD.
Several aspects of this cleverly designed study may be useful to explore to better understand and interpret the findings. Notably, the study was designed to include 216 patients at six centers over a period of 3 years. The authors explained that lack of enrollment led to a sizable downgrade to 122 patients at three psychiatric centers. The lower numbers certainly may have affected the findings and lead to some questions regarding validity and specifically the ability of the statistics to detect differences of clinical significance.
Although not a primary focus of this study, it is curious that the sham light-fluoxetine arm was not statistically different from placebo. This is somewhat surprising, as previous studies have documented the efficacy of fluoxetine in treatment of MDD.7 It may be here that the lower number of subjects was most effective in limiting the ability to detect statistical differences. Of note, other studies looking at antidepressants and placebo have noted a pattern of antidepressant response higher than placebo, primarily in more severely depressed patients and also in studies with multiple antidepressant treatment arms; in other conditions, the antidepressant and placebo rates of response are statistically non-significant, as we see in this study.8,9
It is also interesting that the sham light-fluoxetine arm included use of a deactivated negative ion generator with an audible hum. Although there is no indication that this sham-light itself had a negative effect on results, the design of this study cannot allow this to be ruled out.
The study used fixed doses of both light and fluoxetine. Tapering up the dose of antidepressant medication in non-responders after week 4 is a typical strategy used in clinical practice; allowing clinically indicated dose changes in the study may have uncovered a more robust response. This may hold true for the non-responders to light therapy as well (although there are no clear medically tested guidelines regarding increasing length of time of light exposure to increase response).
The relatively low-risk nature of light treatment is appealing, especially when compared to the known side effects of antidepressants, which include potential for suicidal thoughts to emerge, libido reduction, weight gain, and sleep disruption.10 Both medication and light therapy can lead to the emergence of hypomania in certain patients11; vigilance and appropriate follow-up is important in treatment of depression regardless of the modality.
The question remains whether front-line practitioners should prescribe light exposure in addition to (or in place of) antidepressant medication for adult patients with MDD. This study, while interesting and suggestive, does not give clear medical evidence to support this as a first-line or standalone intervention. Further studies clarifying the role of light exposure and mechanism of action in the treatment of depression should help to “shed more light” and provide clear recommendations.
The importance of treating depression in general is not in contention; effective treatment can limit or reverse the natural tendency of MDD to progress. Using evidence-based, safe, effective, and robust treatments remains an essential key in addressing this disorder. Developing new modalities and treatments can advance the field and reduce the morbidity and mortality associated with MDD. For now, it seems reasonable to tell patients with MDD that light exposure may be helpful for treating non-seasonal depression and that there is a potential for additive effect when combined with conventional antidepressant medication.
REFERENCES
- Parry BL, Maurer EL. Light treatment of mood disorders. Dialogues Clin Neurosci 2003;5:353-365.
- Martensson B, et al. Bright white light therapy in depression: A critical review of the evidence. J Affect Disord 2015;182:1-7.
- Williams JB, Kobak KA. Development and reliability of a structured interview guide for the Montgomery Asberg Depression Rating Scale (SIGMA). Br J Psychiatry 2008;192:52-58. doi: 10.1192/bjp.bp.106.032532.
- World Health Organization. Depression. Available at: http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed Dec. 30, 2015.
- Derek R. Prevalence and clinical course of depression: A review. Clin Psychol Rev 2011;31:1117-1125.
- Borges S, et al. Review of maintenance trials for major depressive disorder: A 25-year perspective from the US Food and Drug Administration. J Clin Psychiatry 2014;75:205-214.
- Rossi A, et al. Fluoxetine: A review on evidence based medicine. Ann Gen Hosp Psychiatry 2004;3:2. Published online: 2004; Feb 12. doi: 10.1186/1475-2832-3-2.
- Khan A, et al. Severity of depression and response to antidepressants and placebo: An analysis of the Food and Drug Administration database. J Clin Psychopharmacol 2002;22:40-45.
- Sinyor M, et al. Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? J Clin Psychiatry 2010;71:270-279.
- Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: Efficacy, protocol, safety, and side effects. CNS Spectr 2005;10:647-663.
- Khawam E, et al. Side effects of antidepressants: An overview. Cleve Clin J Med 2006;73:351-361.
In this four-pronged study comparing the effect of bright light treatment, fluoxetine, a combination of these two interventions, and placebo in patients with major depressive disorder, the combination treatment appears the most consistently effective.
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