Bupropion Sustained released versus Placebo for seasonal affective Disorder

Background: The majority of seasonal affective disorder (SAD) studies have evaluated the use of light or selective serotonin reuptake inhibitors (SSRI). The purpose of the present study was to evaluate bupropion sustained-released (SR), a non-SSRI antidepressant, for the treatment of SAD. Method: Forty-one adults meeting DSM IV criteria for SAD were recruited into a six-week, randomized, double-blind, placebo-controlled trial. Participants started on bupropion SR 150 mg QD (or equivalent placebo pills) and titrated up to 200 mg BID if tolerated by week 4. Participants were evaluated weekly with SIGH-SAD and self-reported Kellner Symptom Questionnaire (SQ). Mixed effects growth models and receiver operating characteristic (ROC) analyses were used to compare treatments. Results: Analysis was done on the 36 participants who completed at least 2 weeks of treatment, as per protocol. Thirty-four participants completed the entire protocol; two participants receiving placebo dropped out during weeks 3 and 5. Sixteen participants (7 male, 9 female, 46.5 + 9.6 years, mean+SD) received bupropion SR and 20 participants (8 males, 12 females, 48.2+8.8 years) received placebo. Participants receiving bupropion SR had a more rapid reduction in atypical SIGH-SAD depressive symptoms and lower depression scores across time on the SQ. ROC analyses revealed that positive effects of bupropion SR on total SIGH-SAD scores were more evident in males than females. Bupropion SR was well tolerated. Conclusion: Bupropion SR may be benefi cial for the treatment of SAD, but larger randomized placebocontrolled studies are warranted. Research Article Bupropion Sustained released versus Placebo for seasonal affective Disorder Martin H Teicher1,2*, Danielle M Webster3 and Steven B Lowen4 1Department of Psychiatry, Harvard Medical School, USA 2Developmental Biopsychiatry Research Program and Clinical Chronobiology Laboratory, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA 3Tufts University, Health Service Department, 124 Professors Row, Medford, MA 02155 4Omni Claim, Inc, 300 Unicorn Park Drive, Woburn, MA 01801, USA Dates: Received: 17 May, 2017; Accepted: 25 May, 2017; Published: 26 May, 2017 *Corresponding author: Martin H Teicher, Mclean Hospital, Developmental Biopsychiatry Research Program, 115 Mill Street, Belmont, MA 02478-9106, USA, Tel: (617) 855-2970; Fax: (617) 855-3712; E-mail:


Introduction
Recurrent major depression with seasonal pattern (SAD) may affect between 1% and 3% of adults living far from the equator [1]. Treatment studies have focused on the use of light.
However, many patients fi nd light therapy inconvenient, or require medications as sole or adjunctive treatment. Relatively few controlled medication trials have been reported. Briefl y, several agents have been found to be ineffective. These include atenolol [2], as a suppressor of melatonin production, melatonin itself [3], levodopa plus carbidopa [4] and cyanocobalamin [5], as an agent that facilitates entrainment of circadian rhythms. Preliminary positive results have been obtained with d-fenfl uramine [6], low-dose morning propranolol [7] and tryptophan [8,9]. Depression Rating Scale or Clinical Global Improvement scores [10]. Using the 29-item modifi ed Structured Hamilton depression Rating Scale (SIGH-SAD) [11], Lam et al. [12], found that fl uoxetine was signifi cantly more effective than placebo based on the percent of participants with a 50% or greater reduction in depression scores (59% vs. 34%), but not in terms of average depression scores. A large-scale Canadian study found that fl uoxetine (20 mg/d) was as effective as 10,000 lux light therapy, but interpretation is clouded by lack of a placebo arm [13]. Moscovitch et al. [14], reported superiority of sertraline over placebo producing a 52% vs. 43% reduction in

Hamilton Depression
Ratings.
An open trial of bupropion for SAD reported marked effi cacy [15]. Since many patients with SAD have symptoms associated with atypical depressions including psychomotor retardation, carbohydrate craving, and hypersomnia, and may have a mild form of bipolar disorder [16], bupropion appears to be a good theoretical choice [17,18]. Bupropion was evaluated in a large multicenter international study for its potential to prevent recurrence of SAD when initiated prior to the fall-winter season.
Bupropion produced a 44% relative risk reduction versus placebo [19] and the FDA subsequently approved bupropion for 009-013. DOI: http://doi.org/10.17352/2455-5460.000016 this purpose. Part of the scientifi c rationale for conducting a trial of bupropion for prophylaxis of SAD was an unpublished randomized double-blind placebo controlled treatment trial. This is a report of the results of that study conducted during the fall/winter 1997/98 and 1998/99.

Method
All participants gave written informed consent for this IRB-approved study after procedures and possible side effects were fully explained. Participants were recruited from the community by newspaper advertisements.
The study was designed as a double-blind, randomized, parallel group placebo control trial. Entry requirements included a diagnosis of Major Depression, Recurrent with Seasonal Pattern based on DSM-IV and Rosenthal-NIMH criteria [16]. Briefl y, these criteria require that individuals have a history of recurrent depressive episodes that regularly recur and remit during specifi c times of the year, this pattern must have lasted at least two years with no nonseasonal episodes and that the number of seasonal episodes substantially outnumber any non-seasonal episodes. Participants also had to have a baseline 29-item Structured Interview Guide for the Hamilton Depression Scale with Atypical Depression Supplement (SIGH SAD) score of at least 20, to be medically healthy and on no medications except hormone replacement therapy (HRT) or oral contraceptives. Participants also had to indicate that they had no plans to travel to tropical locations during the time that there were enrolled in the study. Individuals with anorexia, bulimia or history of seizures were excluded. Potential participants who met these criteria then received a blood test to assess thyroid status and returned 1-2 weeks later for reassessment. On the second baseline assessment they also needed to have a SIGH-SAD score of at least 20 and normal thyroid profi le. Those who did were randomized to drug or placebo.
Effi cacy measurements included interviewer-based SIGH SAD scores [11] and self-reported symptoms of depression on Kellner's Symptom Questionnaire (SQ) [20]. Potential adverse events were assessed each week by inquiring about specifi c side effects including dry mouth, nausea, weight loss, insomnia, anxiety, agitation, seizures, dizziness and constipation.
Following the second baseline measure participants received 6 weeks of treatment on drug or placebo. Bupropion SR was introduced at 150 mg once daily, and titrated to 200 mg twice daily by week 4, if tolerated. Participants receiving placebo followed the same titration schedule.
Placebo-controlled trials of light therapy indicate that conventional analysis of mean improvement on SIGH-SAD scores often fails to detect a signifi cant light-placebo difference [21,22]. Light therapy emerges as superior to placebo, based on percentage of participants showing full clinical remission, and by Receiver-Operating Characteristic (ROC) analysis of the data [22]. Unlike conventional statistical tests, ROC analyses make no assumptions about the distribution of the data or the scaling properties of the measure. It also does not force the investigator to make an arbitrary decision that a specifi c score or percent change criteria is required for improvement or remission. Rather, it portrays the differential pattern of response of patients on drug versus placebo across the entire range of scores. Assuming that there was no difference between drug and placebo then the area under the ROC curve (AUC ROC) would be 0.5, and the ROC curve would follow a straight line from the origin (0,0) to the joint maximum (1,1). Comparing the actual pattern of drug-placebo response to the theoretical null effect line provides a powerful means of detecting a differential pattern of response to drug, and also provides novel insight into the type of therapeutic response obtained. ROC response was analyzed in two ways. First we assessed the signifi cance of the area under the curve, which is equivalent to the Mann-Whitney U test or Wilcoxon rank sum test. Second, we used the Kolmogorov-Smirnov test [23], to examine maximal degree of departure from the null effect chance line to determine if there was a differential pattern of response to drug versus placebo.
The Fisher Exact Test was used to compare percentage of participants meeting remission criteria at endpoint on drug versus placebo. Finally, hierarchical growth models [24], were used to compare drug versus placebo differences in time course of response based on ratings at baseline and during each of the 6 treatment weeks.
Because the sample size was modest and this was a preliminary study we used a directional one-tailed criteria P 1T < 0.05 testing whether participants on bupropion showed a superior response than participants on placebo, or two-tailed directionless criteria of P < 0.1.

Results
Forty-six participants were recruited and came in for their fi rst baseline assessment. Five were excluded from the study P 1T = 0.12). Hierarchical growth curve analysis indicated that the SIGH-SAD total scores were better fi t by a 2-component piecewise growth model with fi rst-order autoregressive (AR1) correlation than by a 1 component AR1 model (LR = 49.3, P < 0.0001), linear model (LR = 64.92, P <0.0001), or quadratic model (LR = 25.7, P < 0.0001). As seen in fi gure 1 there was a marked drop in SIGH-SAD scores from baseline to fi rst posttreatment visit (T1: F 1,212 = 48.50, P < 0.0001) and a gradual reduction from fi rst to sixth post-treatment visit (T2: F 1,212 = 30.33, P < 0.0001). However, there was no signifi cant overall difference between participants receiving bupropion versus placebo (F 1,33 = 0.29, P > 0.5) nor any signifi cant treatment by T1 (F 1 ,212 = 1.85, P = 0.17) or treatment x T2 interactions (F 1,212 = 1.72 P = 0.19).
Total SIGH-SAD score represent the sum of the standard 21-item Hamilton Depression Rating Scale (HDRS-21) plus an 8-item atypical addendum that includes features such as hypersomnia, carbohydrate craving and reverse diurnal variation. These "atypical" features are included in the SIGH-SAD as they tend to better characterize individuals with seasonal depression than more typical depressive symptoms. There was no evidence for medication versus placebo differences on HDRS-21 scores; however there were signifi cant T1 x treatment (F 1,212 = 3.75, P = 0.05) and T2 x treatment (F 1, 212 = 3.19, P < 0.08) interactions on atypical depression scores ( Figure 2).
As seen in fi gure 3, AUC ROC for fi nal SIGH-SAD scores (AUC = 0.548, p = 0.32) was not signifi cant, but there was evidence for a differential pattern of response. The ROC curve deviated signifi cantly from the null effect line with the greatest deviation occurring around fi nal SIGH-SAD scores of 7 (P < 0.05). ROC analysis demonstrated distinctly different drug response patterns in males vs. females. As illustrated in fi gure 3, the ROC curve for males departed signifi cantly from the null effect line, particularly at scores of 7-9. All male participant scores between 4-7 (remission) occurred on drug while all scores between 18-28 (no benefi t) occurred on placebo. In contrast, females showed a divergent response pattern. Virtually all scores between 10-16 (partial response) occurred in women on placebo. Nearly all scores between 3 -7 (remission) and nearly all scores between 17 -26 (no benefi t) occurred on bupropion SR. Hence, women receiving bupropion SR either did quite well or reported more symptoms than women receiving placebo. In comparison with other studies that asked "Have you felt different in any way since your last visit?," we specifi cally inquired about common side effects each week. Overall bupropion SR was well tolerated. The only signifi cant side effect was constipation reported by 6 (37%) participants on bupropion SR and 2 (10%) on placebo (Fisher Exact, P 1T = 0.058).
Interestingly 5 out of 9 females on bupropion SR reported this as a side effect, but constipation was not related to degree of antidepressant response.

Acknowledgments
Supported, in part, by Glaxo Wellcome, Inc, now GlaxoSmithKline, as an investigator initiated study. The company played no role in the design, analysis or reporting of There was no signifi cant overall benefi t of bupropion on SIGH-SAD scores for the entire sample based on area under the ROC curve. However, there was a differential pattern of response to bupropion versus placebo based on Kolmogov-Smirnof analyses, as the distribution of probability scores deviated signifi cantly from the chance -null effect line around SIGH-SAD scores of 7. Males and females showed different patterns of responses. Men showed a potential drug advantage, with a ROC area of 0.652. Men deviated signifi cantly from the null effect line, particularly at scores of 7-9 and 18-22. In contrast, women showed no overall benefi t on bupropion, as some did quite well but others had scores higher than women taking placebo. Number in circles are total SIGH-SAD depression scores at each point.