Replication of scopolamine's antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial

Abstract

Background: We previously reported that intravenous (IV) scopolamine administration produced rapid and robust antidepressant effects in a sample consisting of both unipolar and bipolar depressives. The present study aimed to replicate this finding in an independent sample limited to unipolar depressives.

Methods: Outpatients with major depressive disorder (MDD; n = 23; 22 were included in analyses) participated in a double-blind, placebo-controlled, crossover trial. Subjects were randomized into either a P/S or S/P sequence (P = block of three placebo sessions; S = block of three scopolamine sessions; [4.0 microg/kg IV]). Sessions occurred 3 to 5 days apart, such that time spent in each block lasted 1.5 to 2 weeks and the interval between blocks was 3 to 5 days. The Montgomery-Asberg Depression Rating Scale (MADRS) served as the primary outcome measure.

Results: Following the initial block, the group receiving scopolamine first (S/P) showed a 32% reduction in MADRS scores (p < .001), which exceeded the corresponding change of 6.5% under placebo (P/S; p = .009), confirming the a-priori hypothesis. Improvement was significant at the first evaluation that followed scopolamine administration (p = .011). In Block 2, the P/S group showed a 53% reduction in MADRS scores (p = .001) following scopolamine versus placebo, whereas the reduction seen in S/P subjects who received scopolamine during Block 1 persisted as they received placebo during Block 2. Scopolamine induced drowsiness, blurred vision, dry mouth, light-headedness, and reduced blood pressure, which were sufficiently well tolerated that no subject dropped out because of side effects.

Conclusions: These results replicate previous finding that scopolamine produces a rapid and robust antidepressant response.

Trial registration: ClinicalTrials.gov NCT00369915.

Published by Elsevier Inc.

Figures

Figure 1

Study blocked experimental design reflecting infusion series and assessment sessions for each of the two randomized patient groups. P/S reflects the infusion series of placebo followed by scopolamine; S/P indicated scopolamine followed by placebo.

Figure 2

Mean MADRS scores for the P/S group (yellow bars) and the S/P group (red bars) across eight assessments. P= the placebo sessions and includes a block of 3 assessments of placebo infusions; S= the scopolamine sessions and includes a block of 3 assessments of scopolamine infusions. Two baseline, three block 1 and three block 2 assessments are identified in each panel. Error bars show standard error of the mean. The p-value reflects a significant block by group interaction.

Figure 3

Mean changes in (A) the Hamilton Anxiety Rating Scale (HARS) and (B) the Clinical Global Impressions-Improvement scores (CGI-I) between Study Block 1 versus the Baseline Block (left bar) and between Study Block 2 versus Baseline (right bar). (A) The HARS data showed a nonsignificant trend in the block by group interaction (F=2.6; p=0.10). To accommodate the variation in mean baseline HARS scores between the S/P and P/S groups (20±9 and 18±8, respectively) the effect of scopolamine on anxiety ratings was evaluated within each group separately. In the P/S group, a block-by-assessment analysis indicated differences among study blocks (F=10.4, p=0.005). Anxiety scores in the P/S group were lower in study block 2 as compared to baseline (F=23.0, p=0.001), this effect was significant with the first assessment in block 2 (t=2.7, p=0.022). The difference between baseline and experimental block 1 was not significant (F=2.6, p=0.14). In the S/P group, the block-by-assessment analysis showed a nonsignificant trend toward differing among blocks (F=3.8, p<0.063). In this group the HARS scores evaluated in block 1 were lower than baseline (F=7.17 p=0.023) and the scores in block 2 were lower than baseline (F=8.03, p=0.018) but did not differ from the scores obtained in block 1 (F=1.79, p=0.21), indicating the antianxiety effect persisted as this group received placebo in block 2. (B) The CGI-I data showed a block-by-group interaction (F= 26.3, P, 0.001). The change in CGI scores in the S/P group was greater than the change in the P/S group during block 1 (F=6.61; p=0.018). No group difference was observed in ratings from study block 2 evaluations (F=1.54; p=0.23) suggesting that the magnitude of clinical improvement did not differ after both groups received scopolamine.