Scopolamine in Bipolar Depression

Bipolar disorder is a chronic disabling psychiatric disorder characterized by recurrent episodes of mania or hypomania and depression. Bipolar disorder can be separated into bipolar 1 and bipolar 2 disorders with bipolar 1 disorder characterizing individuals who have episodes of mania and depression, and bipolar 2 disorder characterizing individuals who have episodes of depression with periods of hypomania, but not mania. Bipolar disorder has an estimated prevalence of approximately 1% and a roughly equal gender ratio. Current pharmacological treatments for bipolar disorder and in particular for the management of depressive episodes in bipolar disorder remain sub-optimal, with pharmacological strategies employed to date often only partially effective. In addition to the time duration for treatment response, multiple treatment trials are also often required, thus increasing patient discomfort and distress.Consequently, pharmacological mechanisms that potentially alleviate depressive symptomatology in bipolar disorder and ameliorate patient functioning could present an additional pharmacological strategy for the management of bipolar disorder. A number of recent studies have suggested that Scopolamine, a pan muscarinic (M) receptor antagonist can elicit a rapid anti-depressant response in both major depressive disorder (MDD) and bipolar disorder and thus may present a novel therapeutic strategy, particularly for the management of bipolar disorder, in individuals experiencing depressive episodes. No significant adverse effects were noted with treatment with Scopolamine (intravenously) in these studies.

This antidepressant effect has been rapid in effect in studies where administration was by an intravenous (IV) method.Of note, those clinical trials where efficacy has been demonstrated have been undertaken in the same centre (Mood and Anxieties Disorder Program at the National Institute of Mental Health in Bethesda, MD) with the more recent trials of larger numbers from that centre including individuals that participated in the previous clinical trials. Although beneficial effects have been noted for depressive episodes in both MDD and bipolar disorder, the actual numbers of participants with bipolar disorder has been limited.

Fewer studies have utilised other potential modes of administration for Scopolamine. A previous study of intramuscular scopolamine demonstrated no antidepressant effect whilst one trial of oral scopolamine as an augmentation agent demonstrated an antidepressant effect, albeit this study did not demonstrate a rapid-acting effect as demonstrated in the studies of IV Scopolamine and did not include individuals with bipolar disorder. In addition, oral Scopolamine has very limited bioavailability of ~4 %.Trials relating to administration of Scopolamine utilising a transdermal patch for the management of depressive episodes have yet to be published.

This is a single-site, randomised, double-blind, placebo-controlled, parallel, phase IIb clinical trial. The trial will be sponsored by the National University of Ireland (NUI) Galway and the sponsorship role coordinated by the HRB-Clinical Research facility Galway (CRFG). The site will be University Hospital Galway, Galway and the site activities will also be co-ordinated by the CRFG. Participants will be attending the Galway-Roscommon Mental Health Services, including a specialised bipolar clinic in Galway and referred due to experiencing a depressive episode by their treating clinical team; or patients who have previously attended NUI Galway/HRB-CRFG with an interest to participate/or have participated in research and have indicated a willingness to engage in future research; or patients who approach the research group directly requesting participation.

Trial participants will be adults (both male and female) who have bipolar disorder and are experiencing a depressive episode of at least moderate severity. A diagnosis of bipolar disorder (bipolar 1 or 2 disorder) will be determined by interview with the Structured Clinical Interview for DSM-V (SCID-RV) with severity of the depressive episode assessed using the Hamilton Depression Rating Scale (HDRS) (HDRS ≥14 for study inclusion) at screening.

The primary outcome in this study is the change in severity of depressive symptoms as measured on the Hamilton Depression Rating Scale score (HDRS). Allocating 25 participants to each arm will ensure power ≥85% to detect a 50% lower score on the Hamilton Depression Rating Scale score (HDRS) in the Scopolamine group compared to placebo group. This assumes a loss to follow-up of ≤12%. It is also anticipated that approximately 60 participants will need to be recruited to ensure 50 participants are eligible for randomisation after a placebo run-in.

After a screening Visit (Visit 1); at Visit 2, all participants will receive placebo run-in (100mls of Saline IV). The screening visit (Visit 1) and Visit 2 may occur on the same day. Within 7 days of Visit 2, participants will be randomised (Visit 3) to receive either placebo (n=25) or 4 μg/kg Scopolamine (n=25) IV in 100mls of Saline over 15 minutes at Visits 3 (day 0), 4 (days 2-6) and 5 (days 6-10), with at least 2 days between IV infusions (Visits 2, 3, 4 and 5). Two follow-up visits (Visits 6 and 7) will occur at day 15 (+/-5 days) and day 29 (+/- 7 days).There will be at least 2 days between Visits 5 and 6 and 3 days between Visits 6 and 7. Participants randomised to the placebo group will receive one 15-minute infusion of IV saline,repeated over 3 visits (Visit 3, 4 \& 5). The placebo and active comparators will be indistinguishable from each other.

Participants will be randomly assigned to receive either scopolamine or placebo in a 1:1 ratio. Randomly permuted blocks of sizes 4 and 6 will be used to ensure similar numbers of participants in each arm of the trial.

Randomisation will be stratified by the HDRS score at trial entry (a score of <23 indicating a mild-moderate depressive episode and a score ≥23 indicating a severe depressive episode). A validated randomisation system will be used at Visit 3, (after HDRS and Young Mania Rating Scale (YMRS) are completed) to randomise patients to either arm. This centralised system will ensure allocation concealment; preventing blinded trial staff from knowing which treatment group will be allocated. Blocks of randomly varying length will also reduce the predictability of the allocation sequence.

Effectiveness outcomes will be analysed on an intention-to-treat basis for all participants randomised and with available follow-up data as per their randomised allocation. A per-protocol dataset is not well-defined under multiple treatments, here it could reasonably be defined as those participants who either received at least 1, at least 2 or all 3 IV treatments after randomisation. Sensitivity analyses will thus be performed on the primary outcome to assess efficacy of the treatment compared to placebo by incorporating the original allocation of participants and their level of adherence to treatment. This will involve examining the short term-effect of treatment in a longitudinal model and the overall effect of number of IV treatments received at follow-up visits after the final IV treatment.

For the primary effectiveness analysis of the primary outcome, it is expected that pre-randomisation measurements of the HDRS score will be correlated with the scores obtained at Visit 6 of treatment. The mean scores at Visit 6 will be compared across the study arms using an ANCOVA model. The response variable will be the change in HDRS score from Visit 3 to HDRS at Visit 6 including the HDRS score at Visit 3 as a covariate in the model. The addition of stratifying variables and other variables as covariates will be considered as appropriate and specified in the statistical analysis plan. This analysis will increase the power to detect significant differences between the groups. Inverse probability weighting will be applied to the primary outcome analysis. These weights will be derived based on the inverse of the probability of a patient's data being missing given their pre-randomisation measurements. This will ensure the estimate and inference is more representative of all patients randomised, reducing bias in the estimation of the treatment effect due to participants lost to follow-up and missing data.

Inference regarding the treatment effectiveness will focus on the point estimate, confidence interval and p-value for hypothesis confirmation.