Neurophysiological Changes Associated with Antidepressant Response to Ketamine Not Observed in a Negative Trial of Scopolamine in Major Depressive Disorder

Abstract

Background: This randomized, placebo-controlled, crossover trial examined the antidepressant efficacy of the muscarinic antagonist scopolamine in major depressive disorder subjects with more severe and refractory forms of major depressive disorder relative to previous reports.

Methods: Participants included 23 medication-free major depressive disorder subjects (12 F/11 M, 20-55 years) currently experiencing a major depressive episode. Subjects had scored ≥20 on the Montgomery-Asberg Depression Rating Scale. Following a single-blind, placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 μg/kg) and placebo in a double-blind manner. The primary and secondary outcomes were the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale, respectively. Magnetoencephalography and plasma brain-derived neurotrophic factor concentrations were obtained prior to and after each treatment phase.

Results: As assessed by both the Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale, scopolamine had no significant antidepressant or anxiolytic effects relative to placebo. No significant drug vs placebo effects were seen in magnetoencephalography gamma power or brain-derived neurotrophic factor plasma concentrations, and brain-derived neurotrophic factor changes did not correlate with change in Montgomery-Asberg Depression Rating Scale score in response to scopolamine.

Conclusions: These results do not support the efficacy of scopolamine for more severe or refractory forms of depression. No pre- to post-infusion changes in plasma brain-derived neurotrophic factor were detected, and magnetoencephalography gamma power changed only in the placebo lead-in, suggesting that these biomarker measures were not affected by scopolamine in this cohort. While difficult to interpret given the lack of antidepressant response, the findings suggest that the neurobiological effects of ketamine and scopolamine are at least partly distinct.

Trial registration: ClinicalTrials.gov NCT00369915.

Figures

Figure 1.

Study design. Following a 2-week wash-out and a single-blind placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 μg/kg) and placebo infusions. Block order was randomized and infusions were administered in a double-blind manner. Please note that the last follow-up visit is not represented in this diagram. Missing data: In placebo/scopolamine (P/S) group, Block 2, visit 2: n = 2 missing Montgomery-Asberg Depression Rating Scale (MADRS), n = 4 missing Hamilton Anxiety Rating Scale (HAM-A); in S/P group, Block 0, visits 1 and 2: n = 1 missing HAM-A, Block 1, visit 1: n = 1 missing HAM-A, Block 2, visit 2: n = 2 missing MADRS, n = 4 missing HAM-A.

Figure 2.

Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) scores. Assessments 4 and 7 were excluded from the analysis. Randomization group by block interaction was not significant for either scale. A main effect of block was significant for both scales. Posthoc tests indicated that for MADRS both Block 1 (padj = .02) and Block 2 (padj = .0001) differed from Block 0 but not from one another (Padj = .14). HAM-A scores for Block 1 (Padj = .01) and Block 2 (Padj = .001) differed from Block 0 but not from one another (Padj = .59). P, placebo; S, scopolamine.

Figure 3.

Z-map of the comparison of gamma power in the post-scopolamine vs post-placebo condition. Red indicates increased gamma in the scopolamine condition, and blue indicates decreased gamma in the scopolamine condition.

Figure 4.

Results of a repeated measures model with fixed effects of time, condition, and their interaction. Least square mean estimates (with SE) are plotted. The pre-post change in natural log-transformed brain-derived neurotrophic factor (BDNF) concentrations did not differ between conditions (F(1,42) = 1.26, P = .27).