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A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression
Author’s Accepted Manuscript A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression Magdalena Chojnacka, Anna, Z Antosik Wójcińska, Monika Dominiak, Dorota Bzinkowska, Agnieszka Borzym, Marlena SokółSzawłowska, Gabriela Bodzak-Opolska, Dorota Antoniak, Łukasz Święcicki
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S0165-0327(15)30910-1 http://dx.doi.org/10.1016/j.jad.2016.05.062 JAD8276
To appear in: Journal of Affective Disorders Received date: 8 September 2015 Revised date: 24 May 2016 Accepted date: 25 May 2016 Cite this article as: Magdalena Chojnacka, Anna, Z Antosik - Wójcińska, Monika Dominiak, Dorota Bzinkowska, Agnieszka Borzym, Marlena SokółSzawłowska, Gabriela Bodzak-Opolska, Dorota Antoniak and Łukasz Święcicki, A sham-controlled randomized trial of adjunctive light therapy for non-seasonal d e p r e s s i o n , Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2016.05.062 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression. Short title: Bright light therapy in non-seasonal depression
Authors: 1.Chojnacka, Magdalena; Institute of Psychiatry and Neurology, Department of Affective Disorders 2. Antosik - Wójcińska, Anna, Z; Institute of Psychiatry and Neurology, Department of Affective Disorders 3. Dominiak, Monika; Institute of Psychiatry and Neurology 4. Bzinkowska, Dorota; Institute of Psychiatry and Neurology, Department of Affective Disorders 5. Borzym, Agnieszka; Institute of Psychiatry and Neurology 6. Sokół-Szawłowska, Marlena; Institute of Psychiatry and Neurology 7. Bodzak-Opolska, Gabriela; Institute of Psychiatry and Neurology 8. Antoniak, Dorota; Institute of Psychiatry and Neurology 9 .Święcicki, Łukasz; Institute of Psychiatry and Neurology, Department of Affective Disorders This work was performed at the Department of Affective Disorders; Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland
Corresponding author: Magdalena Chojnacka Department of Affective Disorders Institute of Psychiatry and Neurology, Sobieskiego Street 9 02-957 Warsaw Poland email:[email protected] Telephone contact +48608533806
Summary Background: The aim of the study was to examine the efficacy and safety of morning bright light therapy (BLT) in the treatment of patients with a current major depressive episode (MDE) in bipolar and unipolar disorder without a seasonal pattern. It was a randomized, sham-controlled trial. Methods: Adults, ages 18-70 years were randomized to treatment either with BLT or a sham negative ion generator (as a placebo control). The subjects were required to be on a stable and therapeutic dose of psychotropic medication for at least 4 weeks prior to enrollment and their treatment had to be insufficiently effective. Their clinical state was monitored at the baseline and at the end of treatment. The Hamilton Depression Rating Scale - 21 items (HDRS-21), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDIII), Clinical Global Impression-Severity (CGI-S) and Patient Global Impression (PGI) were used. The results were analysed with an intention-to-treat (ITT) analysis. Results: Ninety-five patients were enrolled (50 diagnosed with bipolar disorder and 45 with unipolar depression). Fifty-two patients were randomized to treatment with BLT and fortythree were in the placebo group (ITT population). Eighty-three subjects completed the study. There were 12 dropouts (5 in the light group and 7 in the placebo group). After 14 days of treatment, a significant improvement was found in all groups (p<0,001). The subjects treated
with BLT did not significantly differ in terms of improvement in HDRS-21 scores at the endpoint when compared to patients treated with placebo (p=0,2). However, further analysis demonstrated significantly higher response (50% v. 27,9%, p=0,02) and remission rates (28,8% v. 11,6%, p=0,04) among patients treated with morning BLT when compared to placebo group. It should be noted that in the population of drug-resistant patients, BLT was more efficacious than placebo. There were no statistically significant differences between unipolar and bipolar disorders (p=0,4). Conclusion: Although overall improvement in HDRS-21 scores were not superior in the BLT group, both response and remission rates were significantly higher among patients treated with BLT relative to those receiving the sham intervention. BLT was also more efficacious than placebo in the population of patients with drug-resistant depression. Further studies to define the subpopulation of patients with non-seasonal depression who may benefit the most from BLT are needed.
Introduction Antidepressants are the mainstay in treating depression. Nevertheless, more than 40% of patients do not respond to the initial trial of antidepressant medication, and at least one-half of these non-responders do not respond to a subsequent medication trial [1]. STAR-D has shown that approximately 30% of patients with major depressive disorder achieve remission after the initial therapy of antidepressant but the likelihood of remission after two rigorous medication trials decreases substantially; remission likely requires more complicated medication regimens for which the existing base of evidence is quite thin [2]. In some patients pharmacotherapy is contraindicated; sometimes there are adverse effects or
interactions with other drugs. Another problem is the lag time to therapeutic effect. This is a big obstacle especially for patients with severe symptoms of depression and accompanying suicidal thoughts. There are ongoing studies that search for new therapeutic strategies for depression. An additional biological treatment option for depressed patients designed either to supplement or replace pharmacotherapy is bright light therapy (BLT). Light therapy was first developed to treat winter seasonal affective disorder (SAD) and has been established as the treatment of choice for the condition [3]. Phototherapy is wellaccepted [4] with early onset of action [5] and has a mild adverse effects profile [6]. The results of a recent study conducted by Lam et al. [7] showed that BLT, both as monotherapy and in combination with fluoxetine, was efficacious and well-tolerated in the treatment of adults with non-seasonal depression. Also, most of the other studies demonstrated the usefulness of BLT in non-seasonal depression, but systematic reviews indicated that evidence for BLT for non-seasonal depression is inconclusive. Even et al. (2008) found an effect of BLT to treat non-seasonal depression, but they refrained from performing a formal meta-analysis due to heterogeneity among the studies in consideration [8]. Similarly, Martensson et al. (2015) conducted a systematic review and found that a metaanalysis would not be meaningful because of heterogeneity between studies [9]. Thus, further trials are needed to offset the varying study designs and relatively small sample sizes of studies conducted to date. Several studies have investigated BLT in bipolar depression. Papatheodorou and Kutcher, 1995 [10] found good or very good treatment responses to BLT among people suffering from bipolar depression. Leibenluft et al., 1995 [11] showed that phototherapy used at midday had a beneficial effect among patients with rapid cycling. In turn, Dauphinais et al., 2012 [12] did not find significant differences between BLT and placebo for individuals with bipolar
depression. Prasko and Horacek, 2002 [13] and Dallaspezia et al., 2012 [14] demonstrated the efficacy of light in the treatment of unipolar depression. Moreover, there are encouraging trials which have shown the effectiveness of light in addressing drug-resistant bipolar depression [15, 16]. Only a few studies have compared the effects of phototherapy in patients with bipolar vs. unipolar depression. Some results suggest that the polarity of affective disorder may influence the efficacy of light therapy. Deltito et al., 1991 [17] used a light treatment in 17 patients with depression in the course of bipolar- or unipolar disorder and found significant improvement in subjects with bipolar depression. Święcicki et al., 2008 [18] treated subjects who had unipolar or bipolar depression with BLT and observed improvement in both groups after 14 days, but the range of improvement was greater among the bipolar patients. Benedetti et al., 2001 [19], in a naturalistic retrospective observation, found that bipolar inpatients in rooms that were exposed to direct sunlight in the morning had a 3,67-day shorter hospital stay than patients in rooms with windows exposed to the West. No effect was found in the population of unipolar inpatients. According to Beauchemin and Hays, 1997 [20], the polarity of affective disorder does not affect the outcome of treatment. The aim of this study was to examine the efficacy and safety of morning BLT when combined with pharmacotherapy in the treatment of patients with a current MDE in the course of bipolar or unipolar affective disorder without seasonal pattern. We used a sham-controlled design to compare the anti-depressive effect of BLT and placebo. Material and methods The participants were recruited directly from the affective disorders clinic at the Institute of Psychiatry and Neurology in Warsaw, Poland. Adult patients aged 18-70, with diagnosis of unipolar or bipolar depression were eligible to participate in the trial. A current depressive
episode was diagnosed in accordance to the ICD-10. The inclusion started in 2009 and lasted until 2012 (4 years). Informed consent was obtained from each participant. The independent bioethics committee of the Institute of Psychiatry and Neurology in Warsaw approved the study (No 37/2008). The patients who qualified for the study were suffering from a current major depressive episode for at least 6 weeks, and were taking antidepressants in sufficient doses for at least 4 weeks prior to their enrollment while registering insufficient treatment effects which was defined as a score of 3 or greater on the Clinical Global Impression Severity (CGI-S) scale. All patients used antidepressants, and some of them were also taking mood stabilizers and/or antipsychotics. None of the patients had any changes to their medications 4 weeks prior to the study. During the 2-week trial period, the subjects continued taking their previous dose of medication. They were not allowed to switch medications or to adjust their dosage. Any change to the medications they were taking resulted in a study discharge. Patients that had been diagnosed with SAD, substance dependence, a severe physical disease making pharmacotherapy or phototherapy impossible, macular degeneration or retinitis pigmentosa, pregnant women, and those breastfeeding were also excluded from the trial. To exclude SAD, the Seasonal Health Questionnaire (SHQ) was used [21]. Using G*Power [22], we calculated that a sample size of 96 participants (48 per group) would reach an 88% power to detect clinically meaningful differences (three points in the HDRS-21 scores) between the groups. With an 88% power and p=0.05 (two-sided test), the authors would be able to detect a moderate standardized effect size of 0.65 [23] between the treatment and placebo groups. The patients were randomly assigned to receive bright white light therapy or placebo. The participants in the treatment arm underwent 30 minutes of BLT at 10000 lux half an hour after they awoke sometime between 8-9 a.m. The device used in the study was a Fotovita, model FV-10, produced by ULTRAVIOL, Poland. This device measures 560x345x120 mm and has
a UV filter. The distance from the screen used in the study was 50 cm. In the absence of consensus on treatment duration, we chose two weeks of light therapy as, according to the results of other studies, this duration is sufficient in producing improvement in SAD [3]. Due to the difficulties in conducting sham-controlled BLT studies [24], the authors decided to use a biologically inactive device created from converted computer equipment. This sham treatment equipment was called a “negative ion generator” by the authors. The device looked like a true ion generator, but it had no therapeutic or non-therapeutic efficacy and no ions were emitted from the device. The “negative ion generator” was also used for a period of two weeks 30 minutes after the subjects woke up every morning around 8-9 a.m. The participants were informed that both methods were effective in treating depression and the goal of the study was to determine which of the methods was more efficacious. The phototherapy or placebo was combined with medication for the duration of the study. None of the pharmacological treatments were changed during this period. Depressive symptoms were assessed at the baseline and at the end of the treatment (after 14 days). The severity of symptoms was evaluated according to the Clinical Global ImpressionSeverity (CGI-S) [25], Hamilton Depression Rating Scale-21 (HDRS-21) [26] and the Montgomery and Asberg Depression Rating Scale (MADRS) [27] objective assessment scales. The patients completed the Beck Depression Inventory (BDI-II) [28] and Patient Global Impression (PGI) [29] self-report instruments. The primary efficacy measure was changes to the HDRS-21 total scores from the baseline to the endpoint. The response (defined as a decrease in baseline HDRS-21 scores of at least 50% or more by the end of the trial) and remission rates (defined as a score of 8 or less on the HDRS-21 at the endpoint [30] ) served as secondary outcome measures. Additionally, to assess the impact of the therapeutic methods on the circadian rhythms of the subjects, the authors used a subscale created particularly for this study. That subscale consisted of
questions extracted from the HDRS scale: No. 4- insomnia early, No. 5-insomnia middle, No. 6- insomnia late, No. 18-diurnal variations. Together with the primary outcomes, the analysis of the subscale was also reported. Some of the participants suffered from drug-resistant depression. Resistance to the therapy was defined as non-responsiveness despite having received two antidepressant medications for a sufficient amount of time and in adequate doses [31]. The aim of this study was also to determine the effects of BLT when combined with antidepressant treatment for this group of patients. During the intervention, the patients were systematically interviewed with regard to possible adverse effects. Tolerance assessments involved describing adverse reactions reported by the participants. Statistical analysis Ninety-five patients were enrolled to the study. Of these, 50 participants had an ICD-10 diagnosis of bipolar disorder in the depressed phase of the illness and 45 participants had unipolar depression. The study results were analyzed using the intention-to-treat (ITT) analysis set with multiple imputation technique for missing values [32]. Variables included to perform the imputation were age, sex, polarity, drug-refractory status, randomization arm, and baseline HDRS-21 score. Fifty-two and forty-three patients were randomized to the BLT and placebo groups respectively (Figure 1). Both the demographic data and mean total scores in the individual assessment scales were evaluated by using descriptive statistics to obtain the mean, standard deviation, and data distribution patterns. For group comparisons analyses of variance, analyses of variance with repetitive measurements, t-testand for evaluation of nominal data chi-square tests were employed. Comparative analyses between the BLT and placebo groups with regard to
polarity, drug-refractory status, and season of participation were also performed. The limit for statistical significance was accepted as p<0,05 and all tests were evaluated in double tail fashion. SPSS Statistics, version 23.0, and the Statistica program, version 7.0, were used to perform the analyses. Results There were no statistically significant differences between the groups at the baseline for demographics, both in relation to the populations treated with BLT and placebo, as to the populations of unipolar and bipolar patients (Table 1). All subjects were Caucasian. All patients were on antidepressants (SSRI-40%, SNRI-20%, TCA-8%, other antidepressants24%), whereas 42% were also on mood stabilizers, and 28% on an antipsychotic. Eighty-three subjects completed the study (47 in the BLT group and 36 in the placebo group). There were 12 dropouts (5 patients in the BLT group and 7 in the placebo group). The reasons for early termination in the BLT and placebo groups were: unwillingness to continue the study (BLT-1, placebo -3), adverse effects (3 vs. 3) and medication switches because of worsening depression (1 vs. 1). Both BLT and placebo were tolerated well. No serious adverse events were reported. The most common reported side effect was slight agitation, affecting 7 patients (BLT-4, placebo-3) and headaches (2 vs. 2). In the light treatment group, 1 subject reported eye strain and sleepiness. In the placebo group, 1 patient became irritable. Most side effects were mild and disappeared during the course of the study. There were no switches to hypomania (according to clinical mental state examination conducted during and at the end of the study). The severity of depression at baseline was moderate/severe and was comparable in both groups (Table 2). Over the course of administering the adjunctive phototherapy or the placebo, the patients’ scores on all the assessment scales used in the present study improved
significantly. As illustrated in Figure 2, both groups showed improvement in the HDRS scale [t(94)=9,3; p<0,001]. An ANOVA showed that there were no significant differences in the magnitude of the change in HDRS and BDI-II scores between the BLT and placebo groups (HDRS - group x time: F(1,93)=1,4; p=0,2, BDI-II - group x time: F(1,93)=1,1; p=0,3). The differences in response and remission rates between the groups were significant (Figure 3). The analysis showed that 50% (26/52) of the patients in the BLT group were responders compared to 27,9% (12/43) in the placebo group (chi2(1)=4,8; p=0,02; phi=-0,22). The remission rates were 28,8% (15/52) in the BLT and 11,6% (5/43) in the placebo group (chi2(1)=4,2; p=0,04; phi =-0,21). Fifty patients with a diagnosis of bipolar disorder in the depressed phase of the illness were enrolled in the study. Of these, 29 were assigned to the BLT group and 21 to the placebo group. Unipolar depression was diagnosed in 45 subjects. Of these, 23 were assigned to the BLT group and 22 to the placebo group. A comparative analysis between the light and placebo groups with regard to polarity was performed. An ANOVA showed that there were no statistically significant differences between the groups (F<1,1; p=0,4). This was illustrated in Figure 4. A subgroup of patients that had been diagnosed with a drug-resistant depression was found in both the BLT and placebo groups (26,9% vs. 23,2% respectively). Drug resistance significantly interacted with time and group in influencing the decrease of HDRS scores (F(1,91)=4; p=0,048). An ANOVA also demonstrated the tendency to importance of the drug resistance factor (F(1,91)=2,11; p=0,07). A graphical analysis showed that the patients with refractory depression in the BLT group had higher HDRS scores at baseline and improved significantly during treatment (Figure 5). An HDRS subscale was created to evaluate selective symptoms of circadian dysfunction. In
this subscale, an ANOVA showed that in the BLT group the improvements were statistically significant in comparison to the placebo group (group x time: F(1, 93)=8,7; p<0,01). However, the patients in the BLT group had significantly higher scores on the subscale at the baseline. This is demonstrated in the graphical analysis (Figure 6). In comparison to the treatment results for the autumn/winter (72%) vs. spring/summer (28%) months, there was no correlation between the season of treatment and the improvement (F(1,91)=0,2; p=0,3). Likewise, analyses revealed no effect of any group of drugs (antidepressants, mood stabilizers or neuroleptics) on the HDRS scores or interaction of drugs with treatment effects. Discussion This is, to our knowledge, the first sham-controlled randomized trial to evaluate the effect of BLT in unipolar vs. bipolar depression. The depressive episodes were diagnosed according to the ICD-10. To exclude seasonality, not necessarily reaching the level of SAD, SHQ was used. Pharmacological treatment was determined at least 4 weeks prior to enrollment. The addition of BLT to the continued administration of antidepressants was, in this study, an augmentation strategy of the current treatment. The abovementioned criteria made it possible to achieve a homogeneous group of patients. The lack of effects caused by the pharmacotherapy used for 4 weeks before enrollment seems to be sufficient proof that the given doses of the drugs in question either did no work or worked insufficiently. However, it is also possible that the beneficial effects of the medications used during the study contributed to the outcomes of the study. In other studies, the duration of treatment with antidepressants before the application of BLT was different. Prasko et al., 2010 [33] added light therapy after 6 weeks, whereas Dauphinais et al. 2012 [12] and Guducu et al., [34] after 2 weeks of antidepressant treatment.
The results of this study show statistically significant improvement for all scales assessing the severity of depression. There were no statistical differences in improvement in the mean HDRS-21 scores at the endpoint among the BLT group when compared to the placebo group. Similar results were obtained by Holsboer-Trachsler et al., 1994 [35], Loving et al., 2005 [36], and Dauphinais et al, 2012 [12]. The results of the presented study did not support that light therapy is more efficacious than placebo in improving depression severity. However, the response and remission rates were significantly higher in the BLT group than in the placebo group. It is also possible that a significant placebo effect may be another factor underlying the results. According to Eastman [24], the issue of placebo responses has been a serious problem in clinical bright light studies. Sometimes antidepressant drugs fail to show superiority over placebo simply because the treatments are not very powerful when compared to the change in the placebo group. Two factors contribute to this change in the placebo group: the placebo effect proper as well as an improvement due to the natural history of remission and fluctuating symptoms levels in the disorder [37]. For this reason, in many randomized controlled trials, the response associated with placebo is similar to those associated with established antidepressants; often, this makes it difficult to interpret results [38]. The response to the placebo across the trials varied, ranging from approximately 10% to more than 50%, and was frequently substantial. In the last two decades, the proportion of patients responding to placebo has clearly increased; this has occurred at a rate of approximately 7% per decade [38]. Furthermore, there is evidence that physical placebos are associated with larger placebo effects than pharmacological ones [39], and that short-term studies suffer from greater placebo effects than long-term studies [40]. In addition, the subjects in our study were informed that both methods were effective in the treatment of depression and that the goal of the study was to determine which of the two methods was more efficacious. According to
reports [41], this information may also increase the placebo effect. If the patients had received information about which of the methods was placebo, it would have been impossible to blind the patients to allocation. Although overall average HDRS scores did not differ between the groups, the secondary analyses revealed significantly higher response and remission rates among patients treated with BLT compared to those treated with placebo. The present study also demonstrated a clinically relevant improvement in terms of dysregulated circadian rhythms in the population treated with phototherapy. Our trial of BLT added to standard pharmacological treatment induced a significant amelioration of these symptoms. This is consistent with findings from previous studies and our knowledge about the chronotherapeuthic methods based on the principles of the circadian rhythm’s organization and sleep physiology. Furthermore, the data suggest that the application of light therapy combined with the administration of antidepressants could be an effective augmentation strategy for patients suffering from drug-resistant non-seasonal depressive episodes. This result is consistent with observations by Benedetti et al., 2005 [15] and Prasko et al., 2010 [33]. This finding could have notable clinical implications, especially when taking into account that current treatment options show only partial responses, if any [42, 43]. However, this must be interpreted with caution because of a small number of patients. It should be noted that in our study, patients with drug-resistant depression in the BLT group had higher HDRS scores at baseline. It is possible that BLT in this group of patients is more efficacious than placebo. These findings call for further studies on BLT for treatment-resistant depression that consider the efficacy of BLT vs placebo in two similar populations with the same baseline severity of depressive symptoms. Drug-resistant depression continues to be a major public concern. For this reason, the development of alternative, non-drug therapeutic strategies that can combat drug-resistant depression are essential.
The trial showed that the polarity of affective disorder does not make a difference on the efficacy of phototherapy. Our findings are compatible with Beauchemin and Hays’s study [20] but different from the trial of Deltito et al., 1991 [17] and Święcicki et al., 2008 [18]. Święcicki found better effects for BLT in patients with bipolar depression when compared to patients with unipolar depression, but it should be noted that among patients with bipolar depression, Święcicki demonstrated a tendency for the participants to be influenced by the season. Such patients were excluded from our study. For this reason also, as the authors claimed, there was no correlation between the season of the treatment and the responses of the participants. Similar effects were obtained by Wirz-Justice et al., 2011 [44]. Our findings indicated that BLT was tolerated well. The most common side effects were slight agitation and headaches. One subject reported eye strain and sleepiness. Three subjects withdrew consent from the study because of adverse reactions. Most side effects were mild and disappeared during the course of the study. These observations are compatible with previous reports [45] and support the safety of light treatment. Limitations In the present study, the treatment was applied for 2 weeks. This is a sufficient amount of time to achieve improvement in SAD [46, 3]. In trials for the effectiveness of BLT in non-seasonal depression, the exposure was conducted for various periods of time. In some of them, the improvement was observed after a week [47, 48] or after 10 days [49]. Benedetti et al, 2003 [50] and Sit et al, 2007 [51] obtained important therapeutic effects after 2 weeks of BLT. However, there are also many reports which have shown effectiveness of light therapy after more than 2 weeks. For instance, Martiny et al., 2005 [5] and Goel et al., 2005 [52] described improvement after 5 weeks of treatment, Sondergaard et al., 2006 [53] – after 4 weeks, and Epperson et al., 2004 [54] found that after 10 weeks of BLT the improvements were
comparable to those achieved with drugs. In future studies, a longer period of BLT treatment should be used. It is possible to state that a longer time of treatment in non-seasonal depression can be associated with better outcomes. However, this issue requires further study. The other important issue is the possibility of using the dosing, duration, and timing of BLT to address side effects and thus improve responses. Shortening the duration of BLT sessions can be helpful in the population of patients who report many adverse effects. This could help decrease the number of drop-outs from the study. Some flexibility would be helpful to obtain the individual optimum dose of BLT. For this study, the inpatients were recruited directly from the affective disorders clinic. Most of them had been diagnosed with moderate or severe depression (often long-term). Some of the treated groups of patients were resistant to previous antidepressant medication with sufficient dosages of antidepressants and various augmentation strategies. The patients were also sometimes diagnosed with comorbid disorders (e.g. personality disorders). Moreover, there are different subtypes of depression in the course of affective disorders. It is not currently known whether people with certain subtypes of mood disorders respond differently to BLT [4, 45, 55]. Nagayama et al., 1991 [55] found that phototherapy is more efficacious for people with atypical depressive symptoms in SAD. According to Terman et al., 1996 [56], more melancholic features in winter depression result in worse responses to light treatment. Such indicators have not been found in non-seasonal depression. Although Haffmans et al., 2009 [57] demonstrated greater efficacy for using BLT to treat atypical non-seasonal depression, other studies do not support this data. Naus et al., 2013 [58] showed that the participants’ depressive symptoms ameliorated after BLT regardless of whether those symptoms had an atypical or melancholic nature. Similarly, Goel et al., 2005 [52] observed that atypical features are not associated with better responses to BLT.
Another limitation of the study was the lack of expectations assessment. This information could be very valuable and would allow the extraction of more information from the results of a study. The expectations could predict treatment responses, but more data should be collected in this area. There are only a few studies utilizing an expectations questionnaire in the field of BLT. ConclusionsThe results of the presented study have revealed no statistical difference in improvement in the mean HDRS-21 scores between the BLT and placebo groups among patients with non-seasonal depression. However, the response and remission rates were significantly higher in the BLT than in the placebo group. Likewise, in the population of drugresistant patients, BLT was found to be more efficacious than placebo. These results suggest that BLT may be more efficacious for a certain subset of patients with non-seasonal depression, and further studies are needed to define this population.
1. Crown WH, Finkelstein S, Berndt ER et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psych 2002; 63: 963-971 2. Gaynes BN, Warden D, Trivedi MH et al. What did STAR*D Teach Us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatric Services 2009; 60: 1439-1445 3. Partonen T: Light therapy. In: Seasonal affective disorder: practice and research. Partonen T, Magnusson A. (red) Oxford University Press, Oxford, 2001 4. Golden RN, Gaynes BN, Ekstrom RD et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. The American journal of psychiatry 2005; 162: 656-62
5. Martiny K, Lunde M, Unden M, et al. Adjunctive bright light in non-seasonal major depression: results from clinician-rated depression scales. Acta Psychiatrica Scandinavica 2005; 112: 117-25 6. Labbate LA, Laffer B, Thibault A at al. Side-effects induced by bright light treatment for seasonal affective disorder. J Clin Psychiatry 1994; 55(5): 189-191 7. Lam RW, Levitt AJ, Levitan RD et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry 2016; 73(1): 56-63 8. Even C, Schroder CM, Friedman S et al. Efficacy of light therapy in nonseasonal depression: a systematic review. J Affect Disord 2008; 108: 11-23 9. Martensson B, Pettersson A, Berglund L at al. Bright white light in depression: a critical review of the evidence. J Affect Disord 2015; 182: 1-7 10. Papatheodorou G, Kutcher S. The effect of adjunctive light therapy on ameliorating breakthrough depressive symptoms in adolescent-onset bipolar disorder. Journal of psychiatry & neuroscience 1995; 20:226-32 11. Leibenluft E, Turner EH, Feldman-Naim S et al. Light therapy in patients with rapid cycling bipolar disorder: preliminary results. Psychopharmacology Bulletin 1995; 31: 705-10 12. Dauphinais DR, Rosenthal JZ, Terman M et al. Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression. Psychiatry Research 2012; 196: 57-61 13. Prasko J, Horacek J, Klaschka J et al. Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression. Neuroendocrinology letters 2002; 23: 109-13
14. Dallaspezia S, Benedetti F, Colombo C et al. Optimized light therapy for non-seasonal major depressive disorder: effects of timing and season. J Affect Disord 2012; 138: 33742 15. Benedetti F, Barbini B, Fulgosi MC et al. Combined total sleep deprivation and light therapy in the treatment of drug-resistant bipolar depression: acute response and longterm remission rates. The Journal of clinical psychiatry 2005; 66: 1535-40 16. Benedetti F, Riccaboni R, Locatelli C, et al. Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drugresistant bipolar depression. J Clin Psychiatry 2014; 75: 133-40 17. Deltito JA, Moline M, Pollak C et al. Effects of phototherapy on non-seasonal unipolar and bipolar depressive spectrum disorders. J Affect Disord 1991; 23: 231-7 18. Święcicki Ł, Lechowicz W, Bzinkowska D et al. Skuteczność leczenia światłem w chorobie afektywnej dwubiegunowej i jednobiegunowej. Post Psychiatr Neurol 2008; 17: 347-51 19. Benedetti F, Colombo C, Barbini B et al.:Morning sunlight reduces length of hospitalization in bipolar depression. J Affect Disord 2001; 62: 221-3 20. Beauchemin KM, Hays P. Phototherapy is a useful adjunct in the treatment of depressed in-patients. Acta Psychiatrica Scandinavica 1997; 95: 424-7 21. Thompson C, Cowan A. The Seasonal Health Questionnaire: a preliminary validation of a new instrument to screen for seasonal affective disorder. J Affect Disord 2001; 64: 89-98 22. Faul F, Erdfelder E, Lang AG et al. G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods 2007; 39: 175-191 23. Cohen J. Statistical Power Analysis for the Behavioral Sciences, Second Edition. Hillsdale, New Jersey 1988: Lawrence Erlbaum Associates
24. Eastman C. What the placebo literature can tell us about phototherapy for SAD. Psychopharmacol Bull 1990; 26: 495-504 25. Guy W. ECDEU Assessment manual for psychpharmacology, revised, US Department of Health, Education, and Welfare, ADDAMHA, NIMH, Rockville 1976, 217-222 26. Hamilton M. A rating scale for depression, Journal of Neurology, Neurosurgery and Psychiatry 1960; 23: 56-62 27. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change, British Journal of Psychiatry 1979; 134: 382-9 28. Beck AT, Steer RA, Brown GK. BDI-II. Beck Depression Inventory. Manual. San Antonio: The Psychological Corporation. 1996 29. W: ECDEU Assessment manual for psychpharmacology, revised, US Department of Health, Education, and Welfare, ADDAMHA, NIMH, Rockville 1976, 223-225 30. Ruhe HG, Dekker JJ, Peen J et al. Clinical use of the Hamilton Depression Rating Scale: is increased efficiency possible? A post hoc comparison of Hamilton Depression Rating Scale, Maier and Bech subscales, Clinical Global Impression, and Symptom Checklist-90 scores. Comprehensive Psychiatry 2005; 46: 417-427 31. Poon SH, Sim K, Sum MY et al. Evidence-based options for treatment-resistant adult bipolar disorder patients. Bipolar Disord 2012; 14: 573-584 32. Rubin DB. Multiple imputation for nonresponse in surveys. New York: Wiley & Sons, 1987 33. Prasko J, Brunovsky M, Latalova K et al. Augmentation of antidepressants with bright light therapy in patients with comorbid depression and borderline personality disorder. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 2010; 154: 355-61
34. Guducu F, Caliyurt O, Vardar E et al. Combination therapy using sertraline with sleep deprivation and light therapy compared to sertraline monotherapy for major depressive disorder. Turk psikiyatri dergisi = Turkish journal of psychiatry 2005; 16: 245-51 35. Holsboer-Trachsler E, Hemmeter U, Hatzinger M et al. Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment--neurobiological and psychometric assessment of course. Journal of psychiatric research 1994; 28: 381-99 36. Loving RT, Kripke DF, Elliott JA et al. Bright light treatment of depression for older adults. BMC psychiatry 2005; 5: 41 37. Andrews G. Placebo response in depression: bane of research, boon to therapy. British J Psychiatry 2001; 178: 192-4 38. Walsh BT, Seidman SN, Sysko R et al. Placebo response in studies of major depression: variable, substantial, and growing. JAMA : the journal of the American Medical Association 2002; 287: 1840-7 39. Meissner K, Kohls N, Colloca L. Introduction to placebo effects in medicine: mechanisms and clinical implications. Philosophical transactions of the Royal Society of London Series B, Biological sciences 2011; 366: 1783-9 40. Rutherford BR, Sneed JR, Roose SP. Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychotherapy and psychosomatics 2009; 78: 172-81 41. Bąbel P. Efekt placebo: fakt czy artefakt. Roczniki psychologiczne 2008; 11: 59-76 42. Fava M, Davidson KG . Definition and epidemiology of treatment-resistant depression. Psychiatric Clinics of North America 1996; 19: 179-200 43. Fawcett J, Barkin RL. Efficacy issues with antidepressants. J Clin Psych 1997;58 (suppl. 6): 32-39
44. Wirz-Justice A, Bader A, Frisch U et al. A randomized, double-blind, placebo-controlled study of light therapy for antepartum depression. J Clin Psych 2011; 72: 986-93 45. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS spectrums 2005; 10: 647-63 46. Labbate LA, Lafer B, Thibault A et al. Influence of phototherapy treatment duration for seasonal affective disorder: outcome at one vs. two weeks. Biol Psychiatry 1995; 38: 747-50 47. Sumaya IC, Rienzi BM, Deegan JF 2nd et al. Bright light treatment decreases depression in institutionalized older adults: a placebo-controlled crossover study. The journals of gerontology Series A, Biological sciences and medical sciences 2001; 56: 356-60 48. Niederhofer H, Von Klitzing K. Bright light treatment as monotherapy of non-seasonal depression for 28 adolescents. Int J Psychiatry Clin Prakt 2012; 16(3): 233-237 49. Wirz-Justice A, Graw P, Roosli H et al. An open trial of light therapy in hospitalised major depression. J Affect Disord 1999; 52: 291-2 50. Benedetti F, Colombo C, Pontiggia A et al. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psych 2003; 64: 648-53 51. Sit D, Wisner KL, Hanusa BH et al. Light therapy for bipolar disorder: a case series in women. Bipolar disorders 2007; 9: 918-27 52. Goel N, Terman M, Terman JS et al. Controlled trial of bright light and negative air ions for chronic depression. Psychological medicine 2005; 35: 945-55 53. Sondergaard MP, Jarden JO, Martiny K et al. Dose response to adjunctive light therapy in citalopram-treated patients with post-stroke depression. A randomised, double-blind pilot study. Psychotherapy and psychosomatics 2006; 75: 244-8
54. Epperson CN, Terman M, Terman JS et al. Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin Psych 2004; 65: 421-5 55. Nagayama H, Sasaki M, Ichii S et al. Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder. J Affect Disord 1991; 23: 185-9 56. Terman M, Amira L, Terman JS et al.:Predictors of response and nonresponse to light treatment for winter depression. The American journal of psychiatry 1996; 153: 1423-9 57. Haffmans PMJ, Leydens P, Hysaj M et al. The effects of light therapy in non-seasonal depression with atypical features. Preliminary results. Society of Light Treatment and Biological Rhytmus. Annual Meeting, Berlin, 2009 58. Naus T, Burger A, Malkoc A et al. Is there a difference in clinical efficacy of bright light therapy for different types of depression? A pilot study. J Affect Disord 2013; 151: 11357
Table and figure legends: Table legends: Table 1. Demographic characteristics of subjects. BLT- bright light therapy.
Gender- Male N(%) Mean age Education - N(%) primary secondary higher Employment - N(%) no student yes Residence - N(%)
Placebo (n=43) 5(12) 51.9+/-12.9
BLT (n=52) 15(29) 53.7+/-14.5
8(19) 22(51) 13(30)
6(12) 25(48) 21(40)
30(70) 0(0) 13(30)
32(62) 3(6) 17(33)
city 38(88) country 5(12) Marital status - (%) married 27(63) single 16(37) Duration of current depressive episode (mean) weeks 10.2+/-7.9 10.3+/-7.3 No of medication trials 2.06±2.07
46(88) 6(12) 34(65) 18(35)
2.23±2.11
Table 2. Baseline and end-point measures of depression severity. MADRS – Montgomery – Asberg Depression Rating Scale, HDRS- Hamilton Depression Rating Scale, BDI- Beck Depression Inventory, CGI- Clinical Global Impression, PGI- Patient Global Impression
Treatment group Scale Bright light therapy
Placebo
Baseline
27,1 ± 9,1
26,5 ± 7,5
End-point
16 ± 10,8
17,0 ± 8,8
Baseline
20,9 ± 6,8
19,9 ± 7,3
End-point
13,7 ± 7,3
14,5 ± 6,7
Baseline
30,8 ± 11,7
30,8 ± 9,4
End-point
18,8 ± 13,2
20,7 ± 10,3
Baseline
4,5 ± 1,0
4,4 ± 0,8
End-point
3,4 ± 1,3
3,5 ± 1,1
MADRS
HDRS
BDI
CGI
PGI
Baseline
5,0 ± 1,1
5,2 ± 1,0
End-point
4,0 ± 1,4
4,2 ± 1,2
Figure legends: Figure 1. Study design Figure 2. Improvement of HDRS scores during two weeks treatment with BLT and placebo. BLT – bright light therapy, HDRS- Hamilton Depression Rating Scale. Figure 3. Response and remission rates for BLT and placebo groups. Response - a decrease in baseline HDRS-21 score of at least 50% or more by the end of the trial, remission -a score of 8 or less on the HDRS-21 at the endpoint . Figure 4. Graphical analysis of the study and control group with regard to diagnosis bipolar vs unipolar depression. Pl-placebo, BLT-bright light therapy, MADRS-b- Montgomery-Asberg Depression Rating Scale baseline, HAMD-b- Hamilton Depression Rating Scale baseline, Beck-b- Beck Depression Inventory baseline, CGI-b- Clinical Global Impression baseline, PGI-b- Patient Global Impression baseline, MADRS-e- Montgomery- Asberg Depression Rating Scale end point, HAMD-e- Hamilton Depression Rating Scale end point, Beck-e- Beck Depression Inventory end point, CGI-e- Clinical Global Impression end point, PGI-e- Patient Global Impression end point. Figure 5. Mean HDRS score at the baseline and at the end point for the groups with or without drug-resistance, treated with BLT and Placebo control. Brackets display the standard deviation. PL- placebo, BLT- bright light therapy, HDRS-b- Hamilton Depression Rating Scale baseline, HDRS-e- Hamilton Depression Rating Scale end point. Figure 6. Mean HDRS- circadian dysfunction subscale score at the baseline and at the end point for the groups treated with BLT and Placebo. Brackets display the standard deviation. PL- placebo, BLT- bright light therapy, HDRS-b- Hamilton Depression Rating Scale baseline, HDRS-e- Hamilton Depression Rating Scale end point, HDRS-s- Hamilton Depression Rating Scale subscale of circadian dysfunction.
Highlights 1. The response and remission rates were higher in the bright light therapy (BLT ) group. 2. No differences in improvement in HDRS-21 scores between BLT and placebo groups. 3. BLT was more efficacious than placebo in the population of drug-resistant patients.
4. Improvements in terms of dysregulated circadian rhythms were superior in BLT group. 5. The polarity of affective disorder did not make a difference on the efficacy of BLT.
Response and remission rates
60,0% 50,0% 40,0% 27,9%
28,8%
20,0% 11,6%
0,0% responders BLT
remitters placebo
PII: DOI: Reference:
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S0165-0327(15)30910-1 http://dx.doi.org/10.1016/j.jad.2016.05.062 JAD8276
To appear in: Journal of Affective Disorders Received date: 8 September 2015 Revised date: 24 May 2016 Accepted date: 25 May 2016 Cite this article as: Magdalena Chojnacka, Anna, Z Antosik - Wójcińska, Monika Dominiak, Dorota Bzinkowska, Agnieszka Borzym, Marlena SokółSzawłowska, Gabriela Bodzak-Opolska, Dorota Antoniak and Łukasz Święcicki, A sham-controlled randomized trial of adjunctive light therapy for non-seasonal d e p r e s s i o n , Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2016.05.062 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression. Short title: Bright light therapy in non-seasonal depression
Authors: 1.Chojnacka, Magdalena; Institute of Psychiatry and Neurology, Department of Affective Disorders 2. Antosik - Wójcińska, Anna, Z; Institute of Psychiatry and Neurology, Department of Affective Disorders 3. Dominiak, Monika; Institute of Psychiatry and Neurology 4. Bzinkowska, Dorota; Institute of Psychiatry and Neurology, Department of Affective Disorders 5. Borzym, Agnieszka; Institute of Psychiatry and Neurology 6. Sokół-Szawłowska, Marlena; Institute of Psychiatry and Neurology 7. Bodzak-Opolska, Gabriela; Institute of Psychiatry and Neurology 8. Antoniak, Dorota; Institute of Psychiatry and Neurology 9 .Święcicki, Łukasz; Institute of Psychiatry and Neurology, Department of Affective Disorders This work was performed at the Department of Affective Disorders; Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland
Corresponding author: Magdalena Chojnacka Department of Affective Disorders Institute of Psychiatry and Neurology, Sobieskiego Street 9 02-957 Warsaw Poland email:[email protected] Telephone contact +48608533806
Summary Background: The aim of the study was to examine the efficacy and safety of morning bright light therapy (BLT) in the treatment of patients with a current major depressive episode (MDE) in bipolar and unipolar disorder without a seasonal pattern. It was a randomized, sham-controlled trial. Methods: Adults, ages 18-70 years were randomized to treatment either with BLT or a sham negative ion generator (as a placebo control). The subjects were required to be on a stable and therapeutic dose of psychotropic medication for at least 4 weeks prior to enrollment and their treatment had to be insufficiently effective. Their clinical state was monitored at the baseline and at the end of treatment. The Hamilton Depression Rating Scale - 21 items (HDRS-21), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDIII), Clinical Global Impression-Severity (CGI-S) and Patient Global Impression (PGI) were used. The results were analysed with an intention-to-treat (ITT) analysis. Results: Ninety-five patients were enrolled (50 diagnosed with bipolar disorder and 45 with unipolar depression). Fifty-two patients were randomized to treatment with BLT and fortythree were in the placebo group (ITT population). Eighty-three subjects completed the study. There were 12 dropouts (5 in the light group and 7 in the placebo group). After 14 days of treatment, a significant improvement was found in all groups (p<0,001). The subjects treated
with BLT did not significantly differ in terms of improvement in HDRS-21 scores at the endpoint when compared to patients treated with placebo (p=0,2). However, further analysis demonstrated significantly higher response (50% v. 27,9%, p=0,02) and remission rates (28,8% v. 11,6%, p=0,04) among patients treated with morning BLT when compared to placebo group. It should be noted that in the population of drug-resistant patients, BLT was more efficacious than placebo. There were no statistically significant differences between unipolar and bipolar disorders (p=0,4). Conclusion: Although overall improvement in HDRS-21 scores were not superior in the BLT group, both response and remission rates were significantly higher among patients treated with BLT relative to those receiving the sham intervention. BLT was also more efficacious than placebo in the population of patients with drug-resistant depression. Further studies to define the subpopulation of patients with non-seasonal depression who may benefit the most from BLT are needed.
Introduction Antidepressants are the mainstay in treating depression. Nevertheless, more than 40% of patients do not respond to the initial trial of antidepressant medication, and at least one-half of these non-responders do not respond to a subsequent medication trial [1]. STAR-D has shown that approximately 30% of patients with major depressive disorder achieve remission after the initial therapy of antidepressant but the likelihood of remission after two rigorous medication trials decreases substantially; remission likely requires more complicated medication regimens for which the existing base of evidence is quite thin [2]. In some patients pharmacotherapy is contraindicated; sometimes there are adverse effects or
interactions with other drugs. Another problem is the lag time to therapeutic effect. This is a big obstacle especially for patients with severe symptoms of depression and accompanying suicidal thoughts. There are ongoing studies that search for new therapeutic strategies for depression. An additional biological treatment option for depressed patients designed either to supplement or replace pharmacotherapy is bright light therapy (BLT). Light therapy was first developed to treat winter seasonal affective disorder (SAD) and has been established as the treatment of choice for the condition [3]. Phototherapy is wellaccepted [4] with early onset of action [5] and has a mild adverse effects profile [6]. The results of a recent study conducted by Lam et al. [7] showed that BLT, both as monotherapy and in combination with fluoxetine, was efficacious and well-tolerated in the treatment of adults with non-seasonal depression. Also, most of the other studies demonstrated the usefulness of BLT in non-seasonal depression, but systematic reviews indicated that evidence for BLT for non-seasonal depression is inconclusive. Even et al. (2008) found an effect of BLT to treat non-seasonal depression, but they refrained from performing a formal meta-analysis due to heterogeneity among the studies in consideration [8]. Similarly, Martensson et al. (2015) conducted a systematic review and found that a metaanalysis would not be meaningful because of heterogeneity between studies [9]. Thus, further trials are needed to offset the varying study designs and relatively small sample sizes of studies conducted to date. Several studies have investigated BLT in bipolar depression. Papatheodorou and Kutcher, 1995 [10] found good or very good treatment responses to BLT among people suffering from bipolar depression. Leibenluft et al., 1995 [11] showed that phototherapy used at midday had a beneficial effect among patients with rapid cycling. In turn, Dauphinais et al., 2012 [12] did not find significant differences between BLT and placebo for individuals with bipolar
depression. Prasko and Horacek, 2002 [13] and Dallaspezia et al., 2012 [14] demonstrated the efficacy of light in the treatment of unipolar depression. Moreover, there are encouraging trials which have shown the effectiveness of light in addressing drug-resistant bipolar depression [15, 16]. Only a few studies have compared the effects of phototherapy in patients with bipolar vs. unipolar depression. Some results suggest that the polarity of affective disorder may influence the efficacy of light therapy. Deltito et al., 1991 [17] used a light treatment in 17 patients with depression in the course of bipolar- or unipolar disorder and found significant improvement in subjects with bipolar depression. Święcicki et al., 2008 [18] treated subjects who had unipolar or bipolar depression with BLT and observed improvement in both groups after 14 days, but the range of improvement was greater among the bipolar patients. Benedetti et al., 2001 [19], in a naturalistic retrospective observation, found that bipolar inpatients in rooms that were exposed to direct sunlight in the morning had a 3,67-day shorter hospital stay than patients in rooms with windows exposed to the West. No effect was found in the population of unipolar inpatients. According to Beauchemin and Hays, 1997 [20], the polarity of affective disorder does not affect the outcome of treatment. The aim of this study was to examine the efficacy and safety of morning BLT when combined with pharmacotherapy in the treatment of patients with a current MDE in the course of bipolar or unipolar affective disorder without seasonal pattern. We used a sham-controlled design to compare the anti-depressive effect of BLT and placebo. Material and methods The participants were recruited directly from the affective disorders clinic at the Institute of Psychiatry and Neurology in Warsaw, Poland. Adult patients aged 18-70, with diagnosis of unipolar or bipolar depression were eligible to participate in the trial. A current depressive
episode was diagnosed in accordance to the ICD-10. The inclusion started in 2009 and lasted until 2012 (4 years). Informed consent was obtained from each participant. The independent bioethics committee of the Institute of Psychiatry and Neurology in Warsaw approved the study (No 37/2008). The patients who qualified for the study were suffering from a current major depressive episode for at least 6 weeks, and were taking antidepressants in sufficient doses for at least 4 weeks prior to their enrollment while registering insufficient treatment effects which was defined as a score of 3 or greater on the Clinical Global Impression Severity (CGI-S) scale. All patients used antidepressants, and some of them were also taking mood stabilizers and/or antipsychotics. None of the patients had any changes to their medications 4 weeks prior to the study. During the 2-week trial period, the subjects continued taking their previous dose of medication. They were not allowed to switch medications or to adjust their dosage. Any change to the medications they were taking resulted in a study discharge. Patients that had been diagnosed with SAD, substance dependence, a severe physical disease making pharmacotherapy or phototherapy impossible, macular degeneration or retinitis pigmentosa, pregnant women, and those breastfeeding were also excluded from the trial. To exclude SAD, the Seasonal Health Questionnaire (SHQ) was used [21]. Using G*Power [22], we calculated that a sample size of 96 participants (48 per group) would reach an 88% power to detect clinically meaningful differences (three points in the HDRS-21 scores) between the groups. With an 88% power and p=0.05 (two-sided test), the authors would be able to detect a moderate standardized effect size of 0.65 [23] between the treatment and placebo groups. The patients were randomly assigned to receive bright white light therapy or placebo. The participants in the treatment arm underwent 30 minutes of BLT at 10000 lux half an hour after they awoke sometime between 8-9 a.m. The device used in the study was a Fotovita, model FV-10, produced by ULTRAVIOL, Poland. This device measures 560x345x120 mm and has
a UV filter. The distance from the screen used in the study was 50 cm. In the absence of consensus on treatment duration, we chose two weeks of light therapy as, according to the results of other studies, this duration is sufficient in producing improvement in SAD [3]. Due to the difficulties in conducting sham-controlled BLT studies [24], the authors decided to use a biologically inactive device created from converted computer equipment. This sham treatment equipment was called a “negative ion generator” by the authors. The device looked like a true ion generator, but it had no therapeutic or non-therapeutic efficacy and no ions were emitted from the device. The “negative ion generator” was also used for a period of two weeks 30 minutes after the subjects woke up every morning around 8-9 a.m. The participants were informed that both methods were effective in treating depression and the goal of the study was to determine which of the methods was more efficacious. The phototherapy or placebo was combined with medication for the duration of the study. None of the pharmacological treatments were changed during this period. Depressive symptoms were assessed at the baseline and at the end of the treatment (after 14 days). The severity of symptoms was evaluated according to the Clinical Global ImpressionSeverity (CGI-S) [25], Hamilton Depression Rating Scale-21 (HDRS-21) [26] and the Montgomery and Asberg Depression Rating Scale (MADRS) [27] objective assessment scales. The patients completed the Beck Depression Inventory (BDI-II) [28] and Patient Global Impression (PGI) [29] self-report instruments. The primary efficacy measure was changes to the HDRS-21 total scores from the baseline to the endpoint. The response (defined as a decrease in baseline HDRS-21 scores of at least 50% or more by the end of the trial) and remission rates (defined as a score of 8 or less on the HDRS-21 at the endpoint [30] ) served as secondary outcome measures. Additionally, to assess the impact of the therapeutic methods on the circadian rhythms of the subjects, the authors used a subscale created particularly for this study. That subscale consisted of
questions extracted from the HDRS scale: No. 4- insomnia early, No. 5-insomnia middle, No. 6- insomnia late, No. 18-diurnal variations. Together with the primary outcomes, the analysis of the subscale was also reported. Some of the participants suffered from drug-resistant depression. Resistance to the therapy was defined as non-responsiveness despite having received two antidepressant medications for a sufficient amount of time and in adequate doses [31]. The aim of this study was also to determine the effects of BLT when combined with antidepressant treatment for this group of patients. During the intervention, the patients were systematically interviewed with regard to possible adverse effects. Tolerance assessments involved describing adverse reactions reported by the participants. Statistical analysis Ninety-five patients were enrolled to the study. Of these, 50 participants had an ICD-10 diagnosis of bipolar disorder in the depressed phase of the illness and 45 participants had unipolar depression. The study results were analyzed using the intention-to-treat (ITT) analysis set with multiple imputation technique for missing values [32]. Variables included to perform the imputation were age, sex, polarity, drug-refractory status, randomization arm, and baseline HDRS-21 score. Fifty-two and forty-three patients were randomized to the BLT and placebo groups respectively (Figure 1). Both the demographic data and mean total scores in the individual assessment scales were evaluated by using descriptive statistics to obtain the mean, standard deviation, and data distribution patterns. For group comparisons analyses of variance, analyses of variance with repetitive measurements, t-testand for evaluation of nominal data chi-square tests were employed. Comparative analyses between the BLT and placebo groups with regard to
polarity, drug-refractory status, and season of participation were also performed. The limit for statistical significance was accepted as p<0,05 and all tests were evaluated in double tail fashion. SPSS Statistics, version 23.0, and the Statistica program, version 7.0, were used to perform the analyses. Results There were no statistically significant differences between the groups at the baseline for demographics, both in relation to the populations treated with BLT and placebo, as to the populations of unipolar and bipolar patients (Table 1). All subjects were Caucasian. All patients were on antidepressants (SSRI-40%, SNRI-20%, TCA-8%, other antidepressants24%), whereas 42% were also on mood stabilizers, and 28% on an antipsychotic. Eighty-three subjects completed the study (47 in the BLT group and 36 in the placebo group). There were 12 dropouts (5 patients in the BLT group and 7 in the placebo group). The reasons for early termination in the BLT and placebo groups were: unwillingness to continue the study (BLT-1, placebo -3), adverse effects (3 vs. 3) and medication switches because of worsening depression (1 vs. 1). Both BLT and placebo were tolerated well. No serious adverse events were reported. The most common reported side effect was slight agitation, affecting 7 patients (BLT-4, placebo-3) and headaches (2 vs. 2). In the light treatment group, 1 subject reported eye strain and sleepiness. In the placebo group, 1 patient became irritable. Most side effects were mild and disappeared during the course of the study. There were no switches to hypomania (according to clinical mental state examination conducted during and at the end of the study). The severity of depression at baseline was moderate/severe and was comparable in both groups (Table 2). Over the course of administering the adjunctive phototherapy or the placebo, the patients’ scores on all the assessment scales used in the present study improved
significantly. As illustrated in Figure 2, both groups showed improvement in the HDRS scale [t(94)=9,3; p<0,001]. An ANOVA showed that there were no significant differences in the magnitude of the change in HDRS and BDI-II scores between the BLT and placebo groups (HDRS - group x time: F(1,93)=1,4; p=0,2, BDI-II - group x time: F(1,93)=1,1; p=0,3). The differences in response and remission rates between the groups were significant (Figure 3). The analysis showed that 50% (26/52) of the patients in the BLT group were responders compared to 27,9% (12/43) in the placebo group (chi2(1)=4,8; p=0,02; phi=-0,22). The remission rates were 28,8% (15/52) in the BLT and 11,6% (5/43) in the placebo group (chi2(1)=4,2; p=0,04; phi =-0,21). Fifty patients with a diagnosis of bipolar disorder in the depressed phase of the illness were enrolled in the study. Of these, 29 were assigned to the BLT group and 21 to the placebo group. Unipolar depression was diagnosed in 45 subjects. Of these, 23 were assigned to the BLT group and 22 to the placebo group. A comparative analysis between the light and placebo groups with regard to polarity was performed. An ANOVA showed that there were no statistically significant differences between the groups (F<1,1; p=0,4). This was illustrated in Figure 4. A subgroup of patients that had been diagnosed with a drug-resistant depression was found in both the BLT and placebo groups (26,9% vs. 23,2% respectively). Drug resistance significantly interacted with time and group in influencing the decrease of HDRS scores (F(1,91)=4; p=0,048). An ANOVA also demonstrated the tendency to importance of the drug resistance factor (F(1,91)=2,11; p=0,07). A graphical analysis showed that the patients with refractory depression in the BLT group had higher HDRS scores at baseline and improved significantly during treatment (Figure 5). An HDRS subscale was created to evaluate selective symptoms of circadian dysfunction. In
this subscale, an ANOVA showed that in the BLT group the improvements were statistically significant in comparison to the placebo group (group x time: F(1, 93)=8,7; p<0,01). However, the patients in the BLT group had significantly higher scores on the subscale at the baseline. This is demonstrated in the graphical analysis (Figure 6). In comparison to the treatment results for the autumn/winter (72%) vs. spring/summer (28%) months, there was no correlation between the season of treatment and the improvement (F(1,91)=0,2; p=0,3). Likewise, analyses revealed no effect of any group of drugs (antidepressants, mood stabilizers or neuroleptics) on the HDRS scores or interaction of drugs with treatment effects. Discussion This is, to our knowledge, the first sham-controlled randomized trial to evaluate the effect of BLT in unipolar vs. bipolar depression. The depressive episodes were diagnosed according to the ICD-10. To exclude seasonality, not necessarily reaching the level of SAD, SHQ was used. Pharmacological treatment was determined at least 4 weeks prior to enrollment. The addition of BLT to the continued administration of antidepressants was, in this study, an augmentation strategy of the current treatment. The abovementioned criteria made it possible to achieve a homogeneous group of patients. The lack of effects caused by the pharmacotherapy used for 4 weeks before enrollment seems to be sufficient proof that the given doses of the drugs in question either did no work or worked insufficiently. However, it is also possible that the beneficial effects of the medications used during the study contributed to the outcomes of the study. In other studies, the duration of treatment with antidepressants before the application of BLT was different. Prasko et al., 2010 [33] added light therapy after 6 weeks, whereas Dauphinais et al. 2012 [12] and Guducu et al., [34] after 2 weeks of antidepressant treatment.
The results of this study show statistically significant improvement for all scales assessing the severity of depression. There were no statistical differences in improvement in the mean HDRS-21 scores at the endpoint among the BLT group when compared to the placebo group. Similar results were obtained by Holsboer-Trachsler et al., 1994 [35], Loving et al., 2005 [36], and Dauphinais et al, 2012 [12]. The results of the presented study did not support that light therapy is more efficacious than placebo in improving depression severity. However, the response and remission rates were significantly higher in the BLT group than in the placebo group. It is also possible that a significant placebo effect may be another factor underlying the results. According to Eastman [24], the issue of placebo responses has been a serious problem in clinical bright light studies. Sometimes antidepressant drugs fail to show superiority over placebo simply because the treatments are not very powerful when compared to the change in the placebo group. Two factors contribute to this change in the placebo group: the placebo effect proper as well as an improvement due to the natural history of remission and fluctuating symptoms levels in the disorder [37]. For this reason, in many randomized controlled trials, the response associated with placebo is similar to those associated with established antidepressants; often, this makes it difficult to interpret results [38]. The response to the placebo across the trials varied, ranging from approximately 10% to more than 50%, and was frequently substantial. In the last two decades, the proportion of patients responding to placebo has clearly increased; this has occurred at a rate of approximately 7% per decade [38]. Furthermore, there is evidence that physical placebos are associated with larger placebo effects than pharmacological ones [39], and that short-term studies suffer from greater placebo effects than long-term studies [40]. In addition, the subjects in our study were informed that both methods were effective in the treatment of depression and that the goal of the study was to determine which of the two methods was more efficacious. According to
reports [41], this information may also increase the placebo effect. If the patients had received information about which of the methods was placebo, it would have been impossible to blind the patients to allocation. Although overall average HDRS scores did not differ between the groups, the secondary analyses revealed significantly higher response and remission rates among patients treated with BLT compared to those treated with placebo. The present study also demonstrated a clinically relevant improvement in terms of dysregulated circadian rhythms in the population treated with phototherapy. Our trial of BLT added to standard pharmacological treatment induced a significant amelioration of these symptoms. This is consistent with findings from previous studies and our knowledge about the chronotherapeuthic methods based on the principles of the circadian rhythm’s organization and sleep physiology. Furthermore, the data suggest that the application of light therapy combined with the administration of antidepressants could be an effective augmentation strategy for patients suffering from drug-resistant non-seasonal depressive episodes. This result is consistent with observations by Benedetti et al., 2005 [15] and Prasko et al., 2010 [33]. This finding could have notable clinical implications, especially when taking into account that current treatment options show only partial responses, if any [42, 43]. However, this must be interpreted with caution because of a small number of patients. It should be noted that in our study, patients with drug-resistant depression in the BLT group had higher HDRS scores at baseline. It is possible that BLT in this group of patients is more efficacious than placebo. These findings call for further studies on BLT for treatment-resistant depression that consider the efficacy of BLT vs placebo in two similar populations with the same baseline severity of depressive symptoms. Drug-resistant depression continues to be a major public concern. For this reason, the development of alternative, non-drug therapeutic strategies that can combat drug-resistant depression are essential.
The trial showed that the polarity of affective disorder does not make a difference on the efficacy of phototherapy. Our findings are compatible with Beauchemin and Hays’s study [20] but different from the trial of Deltito et al., 1991 [17] and Święcicki et al., 2008 [18]. Święcicki found better effects for BLT in patients with bipolar depression when compared to patients with unipolar depression, but it should be noted that among patients with bipolar depression, Święcicki demonstrated a tendency for the participants to be influenced by the season. Such patients were excluded from our study. For this reason also, as the authors claimed, there was no correlation between the season of the treatment and the responses of the participants. Similar effects were obtained by Wirz-Justice et al., 2011 [44]. Our findings indicated that BLT was tolerated well. The most common side effects were slight agitation and headaches. One subject reported eye strain and sleepiness. Three subjects withdrew consent from the study because of adverse reactions. Most side effects were mild and disappeared during the course of the study. These observations are compatible with previous reports [45] and support the safety of light treatment. Limitations In the present study, the treatment was applied for 2 weeks. This is a sufficient amount of time to achieve improvement in SAD [46, 3]. In trials for the effectiveness of BLT in non-seasonal depression, the exposure was conducted for various periods of time. In some of them, the improvement was observed after a week [47, 48] or after 10 days [49]. Benedetti et al, 2003 [50] and Sit et al, 2007 [51] obtained important therapeutic effects after 2 weeks of BLT. However, there are also many reports which have shown effectiveness of light therapy after more than 2 weeks. For instance, Martiny et al., 2005 [5] and Goel et al., 2005 [52] described improvement after 5 weeks of treatment, Sondergaard et al., 2006 [53] – after 4 weeks, and Epperson et al., 2004 [54] found that after 10 weeks of BLT the improvements were
comparable to those achieved with drugs. In future studies, a longer period of BLT treatment should be used. It is possible to state that a longer time of treatment in non-seasonal depression can be associated with better outcomes. However, this issue requires further study. The other important issue is the possibility of using the dosing, duration, and timing of BLT to address side effects and thus improve responses. Shortening the duration of BLT sessions can be helpful in the population of patients who report many adverse effects. This could help decrease the number of drop-outs from the study. Some flexibility would be helpful to obtain the individual optimum dose of BLT. For this study, the inpatients were recruited directly from the affective disorders clinic. Most of them had been diagnosed with moderate or severe depression (often long-term). Some of the treated groups of patients were resistant to previous antidepressant medication with sufficient dosages of antidepressants and various augmentation strategies. The patients were also sometimes diagnosed with comorbid disorders (e.g. personality disorders). Moreover, there are different subtypes of depression in the course of affective disorders. It is not currently known whether people with certain subtypes of mood disorders respond differently to BLT [4, 45, 55]. Nagayama et al., 1991 [55] found that phototherapy is more efficacious for people with atypical depressive symptoms in SAD. According to Terman et al., 1996 [56], more melancholic features in winter depression result in worse responses to light treatment. Such indicators have not been found in non-seasonal depression. Although Haffmans et al., 2009 [57] demonstrated greater efficacy for using BLT to treat atypical non-seasonal depression, other studies do not support this data. Naus et al., 2013 [58] showed that the participants’ depressive symptoms ameliorated after BLT regardless of whether those symptoms had an atypical or melancholic nature. Similarly, Goel et al., 2005 [52] observed that atypical features are not associated with better responses to BLT.
Another limitation of the study was the lack of expectations assessment. This information could be very valuable and would allow the extraction of more information from the results of a study. The expectations could predict treatment responses, but more data should be collected in this area. There are only a few studies utilizing an expectations questionnaire in the field of BLT. ConclusionsThe results of the presented study have revealed no statistical difference in improvement in the mean HDRS-21 scores between the BLT and placebo groups among patients with non-seasonal depression. However, the response and remission rates were significantly higher in the BLT than in the placebo group. Likewise, in the population of drugresistant patients, BLT was found to be more efficacious than placebo. These results suggest that BLT may be more efficacious for a certain subset of patients with non-seasonal depression, and further studies are needed to define this population.
1. Crown WH, Finkelstein S, Berndt ER et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psych 2002; 63: 963-971 2. Gaynes BN, Warden D, Trivedi MH et al. What did STAR*D Teach Us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatric Services 2009; 60: 1439-1445 3. Partonen T: Light therapy. In: Seasonal affective disorder: practice and research. Partonen T, Magnusson A. (red) Oxford University Press, Oxford, 2001 4. Golden RN, Gaynes BN, Ekstrom RD et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. The American journal of psychiatry 2005; 162: 656-62
5. Martiny K, Lunde M, Unden M, et al. Adjunctive bright light in non-seasonal major depression: results from clinician-rated depression scales. Acta Psychiatrica Scandinavica 2005; 112: 117-25 6. Labbate LA, Laffer B, Thibault A at al. Side-effects induced by bright light treatment for seasonal affective disorder. J Clin Psychiatry 1994; 55(5): 189-191 7. Lam RW, Levitt AJ, Levitan RD et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry 2016; 73(1): 56-63 8. Even C, Schroder CM, Friedman S et al. Efficacy of light therapy in nonseasonal depression: a systematic review. J Affect Disord 2008; 108: 11-23 9. Martensson B, Pettersson A, Berglund L at al. Bright white light in depression: a critical review of the evidence. J Affect Disord 2015; 182: 1-7 10. Papatheodorou G, Kutcher S. The effect of adjunctive light therapy on ameliorating breakthrough depressive symptoms in adolescent-onset bipolar disorder. Journal of psychiatry & neuroscience 1995; 20:226-32 11. Leibenluft E, Turner EH, Feldman-Naim S et al. Light therapy in patients with rapid cycling bipolar disorder: preliminary results. Psychopharmacology Bulletin 1995; 31: 705-10 12. Dauphinais DR, Rosenthal JZ, Terman M et al. Controlled trial of safety and efficacy of bright light therapy vs. negative air ions in patients with bipolar depression. Psychiatry Research 2012; 196: 57-61 13. Prasko J, Horacek J, Klaschka J et al. Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression. Neuroendocrinology letters 2002; 23: 109-13
14. Dallaspezia S, Benedetti F, Colombo C et al. Optimized light therapy for non-seasonal major depressive disorder: effects of timing and season. J Affect Disord 2012; 138: 33742 15. Benedetti F, Barbini B, Fulgosi MC et al. Combined total sleep deprivation and light therapy in the treatment of drug-resistant bipolar depression: acute response and longterm remission rates. The Journal of clinical psychiatry 2005; 66: 1535-40 16. Benedetti F, Riccaboni R, Locatelli C, et al. Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drugresistant bipolar depression. J Clin Psychiatry 2014; 75: 133-40 17. Deltito JA, Moline M, Pollak C et al. Effects of phototherapy on non-seasonal unipolar and bipolar depressive spectrum disorders. J Affect Disord 1991; 23: 231-7 18. Święcicki Ł, Lechowicz W, Bzinkowska D et al. Skuteczność leczenia światłem w chorobie afektywnej dwubiegunowej i jednobiegunowej. Post Psychiatr Neurol 2008; 17: 347-51 19. Benedetti F, Colombo C, Barbini B et al.:Morning sunlight reduces length of hospitalization in bipolar depression. J Affect Disord 2001; 62: 221-3 20. Beauchemin KM, Hays P. Phototherapy is a useful adjunct in the treatment of depressed in-patients. Acta Psychiatrica Scandinavica 1997; 95: 424-7 21. Thompson C, Cowan A. The Seasonal Health Questionnaire: a preliminary validation of a new instrument to screen for seasonal affective disorder. J Affect Disord 2001; 64: 89-98 22. Faul F, Erdfelder E, Lang AG et al. G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods 2007; 39: 175-191 23. Cohen J. Statistical Power Analysis for the Behavioral Sciences, Second Edition. Hillsdale, New Jersey 1988: Lawrence Erlbaum Associates
24. Eastman C. What the placebo literature can tell us about phototherapy for SAD. Psychopharmacol Bull 1990; 26: 495-504 25. Guy W. ECDEU Assessment manual for psychpharmacology, revised, US Department of Health, Education, and Welfare, ADDAMHA, NIMH, Rockville 1976, 217-222 26. Hamilton M. A rating scale for depression, Journal of Neurology, Neurosurgery and Psychiatry 1960; 23: 56-62 27. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change, British Journal of Psychiatry 1979; 134: 382-9 28. Beck AT, Steer RA, Brown GK. BDI-II. Beck Depression Inventory. Manual. San Antonio: The Psychological Corporation. 1996 29. W: ECDEU Assessment manual for psychpharmacology, revised, US Department of Health, Education, and Welfare, ADDAMHA, NIMH, Rockville 1976, 223-225 30. Ruhe HG, Dekker JJ, Peen J et al. Clinical use of the Hamilton Depression Rating Scale: is increased efficiency possible? A post hoc comparison of Hamilton Depression Rating Scale, Maier and Bech subscales, Clinical Global Impression, and Symptom Checklist-90 scores. Comprehensive Psychiatry 2005; 46: 417-427 31. Poon SH, Sim K, Sum MY et al. Evidence-based options for treatment-resistant adult bipolar disorder patients. Bipolar Disord 2012; 14: 573-584 32. Rubin DB. Multiple imputation for nonresponse in surveys. New York: Wiley & Sons, 1987 33. Prasko J, Brunovsky M, Latalova K et al. Augmentation of antidepressants with bright light therapy in patients with comorbid depression and borderline personality disorder. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 2010; 154: 355-61
34. Guducu F, Caliyurt O, Vardar E et al. Combination therapy using sertraline with sleep deprivation and light therapy compared to sertraline monotherapy for major depressive disorder. Turk psikiyatri dergisi = Turkish journal of psychiatry 2005; 16: 245-51 35. Holsboer-Trachsler E, Hemmeter U, Hatzinger M et al. Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment--neurobiological and psychometric assessment of course. Journal of psychiatric research 1994; 28: 381-99 36. Loving RT, Kripke DF, Elliott JA et al. Bright light treatment of depression for older adults. BMC psychiatry 2005; 5: 41 37. Andrews G. Placebo response in depression: bane of research, boon to therapy. British J Psychiatry 2001; 178: 192-4 38. Walsh BT, Seidman SN, Sysko R et al. Placebo response in studies of major depression: variable, substantial, and growing. JAMA : the journal of the American Medical Association 2002; 287: 1840-7 39. Meissner K, Kohls N, Colloca L. Introduction to placebo effects in medicine: mechanisms and clinical implications. Philosophical transactions of the Royal Society of London Series B, Biological sciences 2011; 366: 1783-9 40. Rutherford BR, Sneed JR, Roose SP. Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychotherapy and psychosomatics 2009; 78: 172-81 41. Bąbel P. Efekt placebo: fakt czy artefakt. Roczniki psychologiczne 2008; 11: 59-76 42. Fava M, Davidson KG . Definition and epidemiology of treatment-resistant depression. Psychiatric Clinics of North America 1996; 19: 179-200 43. Fawcett J, Barkin RL. Efficacy issues with antidepressants. J Clin Psych 1997;58 (suppl. 6): 32-39
44. Wirz-Justice A, Bader A, Frisch U et al. A randomized, double-blind, placebo-controlled study of light therapy for antepartum depression. J Clin Psych 2011; 72: 986-93 45. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS spectrums 2005; 10: 647-63 46. Labbate LA, Lafer B, Thibault A et al. Influence of phototherapy treatment duration for seasonal affective disorder: outcome at one vs. two weeks. Biol Psychiatry 1995; 38: 747-50 47. Sumaya IC, Rienzi BM, Deegan JF 2nd et al. Bright light treatment decreases depression in institutionalized older adults: a placebo-controlled crossover study. The journals of gerontology Series A, Biological sciences and medical sciences 2001; 56: 356-60 48. Niederhofer H, Von Klitzing K. Bright light treatment as monotherapy of non-seasonal depression for 28 adolescents. Int J Psychiatry Clin Prakt 2012; 16(3): 233-237 49. Wirz-Justice A, Graw P, Roosli H et al. An open trial of light therapy in hospitalised major depression. J Affect Disord 1999; 52: 291-2 50. Benedetti F, Colombo C, Pontiggia A et al. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psych 2003; 64: 648-53 51. Sit D, Wisner KL, Hanusa BH et al. Light therapy for bipolar disorder: a case series in women. Bipolar disorders 2007; 9: 918-27 52. Goel N, Terman M, Terman JS et al. Controlled trial of bright light and negative air ions for chronic depression. Psychological medicine 2005; 35: 945-55 53. Sondergaard MP, Jarden JO, Martiny K et al. Dose response to adjunctive light therapy in citalopram-treated patients with post-stroke depression. A randomised, double-blind pilot study. Psychotherapy and psychosomatics 2006; 75: 244-8
54. Epperson CN, Terman M, Terman JS et al. Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin Psych 2004; 65: 421-5 55. Nagayama H, Sasaki M, Ichii S et al. Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder. J Affect Disord 1991; 23: 185-9 56. Terman M, Amira L, Terman JS et al.:Predictors of response and nonresponse to light treatment for winter depression. The American journal of psychiatry 1996; 153: 1423-9 57. Haffmans PMJ, Leydens P, Hysaj M et al. The effects of light therapy in non-seasonal depression with atypical features. Preliminary results. Society of Light Treatment and Biological Rhytmus. Annual Meeting, Berlin, 2009 58. Naus T, Burger A, Malkoc A et al. Is there a difference in clinical efficacy of bright light therapy for different types of depression? A pilot study. J Affect Disord 2013; 151: 11357
Table and figure legends: Table legends: Table 1. Demographic characteristics of subjects. BLT- bright light therapy.
Gender- Male N(%) Mean age Education - N(%) primary secondary higher Employment - N(%) no student yes Residence - N(%)
Placebo (n=43) 5(12) 51.9+/-12.9
BLT (n=52) 15(29) 53.7+/-14.5
8(19) 22(51) 13(30)
6(12) 25(48) 21(40)
30(70) 0(0) 13(30)
32(62) 3(6) 17(33)
city 38(88) country 5(12) Marital status - (%) married 27(63) single 16(37) Duration of current depressive episode (mean) weeks 10.2+/-7.9 10.3+/-7.3 No of medication trials 2.06±2.07
46(88) 6(12) 34(65) 18(35)
2.23±2.11
Table 2. Baseline and end-point measures of depression severity. MADRS – Montgomery – Asberg Depression Rating Scale, HDRS- Hamilton Depression Rating Scale, BDI- Beck Depression Inventory, CGI- Clinical Global Impression, PGI- Patient Global Impression
Treatment group Scale Bright light therapy
Placebo
Baseline
27,1 ± 9,1
26,5 ± 7,5
End-point
16 ± 10,8
17,0 ± 8,8
Baseline
20,9 ± 6,8
19,9 ± 7,3
End-point
13,7 ± 7,3
14,5 ± 6,7
Baseline
30,8 ± 11,7
30,8 ± 9,4
End-point
18,8 ± 13,2
20,7 ± 10,3
Baseline
4,5 ± 1,0
4,4 ± 0,8
End-point
3,4 ± 1,3
3,5 ± 1,1
MADRS
HDRS
BDI
CGI
PGI
Baseline
5,0 ± 1,1
5,2 ± 1,0
End-point
4,0 ± 1,4
4,2 ± 1,2
Figure legends: Figure 1. Study design Figure 2. Improvement of HDRS scores during two weeks treatment with BLT and placebo. BLT – bright light therapy, HDRS- Hamilton Depression Rating Scale. Figure 3. Response and remission rates for BLT and placebo groups. Response - a decrease in baseline HDRS-21 score of at least 50% or more by the end of the trial, remission -a score of 8 or less on the HDRS-21 at the endpoint . Figure 4. Graphical analysis of the study and control group with regard to diagnosis bipolar vs unipolar depression. Pl-placebo, BLT-bright light therapy, MADRS-b- Montgomery-Asberg Depression Rating Scale baseline, HAMD-b- Hamilton Depression Rating Scale baseline, Beck-b- Beck Depression Inventory baseline, CGI-b- Clinical Global Impression baseline, PGI-b- Patient Global Impression baseline, MADRS-e- Montgomery- Asberg Depression Rating Scale end point, HAMD-e- Hamilton Depression Rating Scale end point, Beck-e- Beck Depression Inventory end point, CGI-e- Clinical Global Impression end point, PGI-e- Patient Global Impression end point. Figure 5. Mean HDRS score at the baseline and at the end point for the groups with or without drug-resistance, treated with BLT and Placebo control. Brackets display the standard deviation. PL- placebo, BLT- bright light therapy, HDRS-b- Hamilton Depression Rating Scale baseline, HDRS-e- Hamilton Depression Rating Scale end point. Figure 6. Mean HDRS- circadian dysfunction subscale score at the baseline and at the end point for the groups treated with BLT and Placebo. Brackets display the standard deviation. PL- placebo, BLT- bright light therapy, HDRS-b- Hamilton Depression Rating Scale baseline, HDRS-e- Hamilton Depression Rating Scale end point, HDRS-s- Hamilton Depression Rating Scale subscale of circadian dysfunction.
Highlights 1. The response and remission rates were higher in the bright light therapy (BLT ) group. 2. No differences in improvement in HDRS-21 scores between BLT and placebo groups. 3. BLT was more efficacious than placebo in the population of drug-resistant patients.
4. Improvements in terms of dysregulated circadian rhythms were superior in BLT group. 5. The polarity of affective disorder did not make a difference on the efficacy of BLT.
Response and remission rates
60,0% 50,0% 40,0% 27,9%
28,8%
20,0% 11,6%
0,0% responders BLT
remitters placebo