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.

Background The intravenous administration of scopolamine produces rapid antidepressant effects. Generally, failing multiple previous antidepressant trials is associated with a poor prognosis for response to future medications. This study evaluated whether treatment history predicts antidepressant response to scopolamine. Methods Treatment resistant patients (2 failed medication trials) (n= 31) and treatment naïve patients (no exposure to psychotropic medication) (n=31) with recurrent major depressive or bipolar disorder participated in a double-blind, placebo-controlled, crossover clinical trial. Following a placebo lead-in, participants randomly received P/S or S/P (P= 3 placebo; S= 3 scopolamine (4ug/kg) sessions 3 to 5 days apart). The Montgomery–Asberg Depression Rating Scale (MADRS) was the primary outcome measure. A linear mixed model was used to examine the interaction between clinical response and treatment history, adjusting for baseline MADRS. Results Treatment resistant and treatment naïve subjects combined responded significantly to scopolamine compared to placebo (F=15.06, p<0.001). Reduction in depressive symptoms was significant by the first post-scopolamine session (F=42.75, p< 0.001). A treatment history by scopolamine session interaction (F=3.37, p=0.04) indicated treatment naïve subjects had lower MADRS scores than treatment resistant patients; this was significant after the second scopolamine infusion (t=2.15, p=0.03). Limitations Post-hoc analysis. Also, we used a single regimen to administer scopolamine, and smokers were excluded from the sample, limiting generalizability. Conclusions Treatment naïve and treatment resistant patients showed improved clinical symptoms following scopolamine, while those who were treatment naïve showed greater improvement. Scopolamine rapidly reduces symptoms in both treatment history groups, and demonstrates sustained improvement even in treatment resistant patients.

P3 amplitude reductions, commonly elicited in oddball paradigms, have been associated with both internalizing (e.g., depression and anxiety) and externalizing problems (e.g., substance use, aggression, and impulsivity). Recent factor analytic models have focused on the shared variance between internalizing and externalizing problems as a potentially important separable psychopathology construct (a general psychopathology factor, or p‐factor). To assess neurophysiological markers of this shared variance, we examined P3 amplitude to target and novel stimuli in an undergraduate sample with a range of internalizing and externalizing problems. Participants (N = 125) completed a rotated heads visual oddball paradigm, with IAPS pictures serving as infrequent novel stimuli. Results replicated P3 amplitude reduction relative to both target and novel stimuli separately for internalizing and externalizing problems, and found that the shared variance across internalizing and externalizing was significantly related to lower P3 amplitude to novels, targets, and a factor score of target and novel P3 measures. The present results are consistent with the interpretation that a general or shared problem behavior factor accounts for much of the associations between reduced P3 amplitude and internalizing and externalizing problems.

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