Antidepressant treatment history as a predictor of response to scopolamine: clinical implications

Abstract

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.

Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity

“…In addition, a follow-up study indicated that females show a significantly greater antidepressant and antianxiety effect following scopolamine treatment compared to males [87]. Interestingly the antidepressant effects of scopolamine appear to be increased with repeated administration in patients with no prior antidepressant treatment history though treatment-resistant patients still show significant reductions in depressive symptoms [88]. Moreover, an early study using other routes (i.e., intramuscular) and dosing regimens suggest that scopolamine can produce antidepressant effects within several hours after drug treatment [89].…”

A randomised, double-blind, active placebo-controlled, parallel groups, dose-response study of scopolamine hydrobromide (4–6 μg/kg) in patients with major depressive disorder

“…The same research group replicated the findings in an independent patient sample consisting only of unipolar depressed patients [6]. By pooling data from the previous two studies and recruiting additional participants, the authors found slightly larger antidepressant effects in women [7] along with antidepressant effects in both treatment-naïve and treatment-resistant depressed patients [8]. However, a recent study utilising an independent participant sample found no significant antidepressant effect compared to placebo-though the authors noted that their population was more severely depressed and treatment-resistant than previous studies [9].…”

“…To date, a crossover design has been used which was too short (3-4 days) to adequately account for carryover effects [5][6][7][8][9]. The antidepressant effects of scopolamine from the first block of triplicate infusions are clearly evident in the psychiatric measures of antidepressant response leading into the second block of triplicate saline placebo infusions [5][6][7][8][9]. Not only does this introduce an unwanted carryover effect in the placebo data, but it also does not characterise the expected antidepressant duration of scopolamine, a parameter established in other rapid acting antidepressants such as ketamine [10].…”

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

“…It has been found to rapidly (within 3 days) and robustly decrease symptoms of depression and anxiety in both unipolar and bipolar patients with treatment-naive and resistant depression, [42][43][44] though those with treatment-naive depression showed greater improvements. 45 Interestingly, though both men and women experience rapid antidepressant and anxiolytic effects following scopolamine, effects appear to be greater in women. 46 However, similar with ketamine, studies on how to maintain short-term gains seen with intravenous scopolamine are lacking.…”