Major Depressive Disorder Clinical Trial
Official title:
A Double-Blind Placebo-Controlled Trial of Dextromethorphan for Treatment of Major Depressive Disorder
A proof-of-concept study to determine the antidepressant potential of Dextromethorphan for treating depression associated with Major Depressive Disorder in inpatients.
The proposed study is a double-blind, placebo-controlled, fixed-dose randomized clinical
trial to evaluate the effects of oral Dextromethorphan on psychiatric inpatients hospitalized
with Major Depressive Disorder on self and examiner rated inventories of depression. The
primary outcome measures will be change in depression symptoms measured with the
examiner-rated Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcome measures
will be depression/anxiety/mood indices measured with subject and examiner-rated inventories
including the Beck Depression Inventory-II (BDI), the State-Trait Anxiety Inventory (STAI),
and the Clinical Global Impressions Scale (CGI). These additional scales will be used to more
comprehensively capture any effects on mood and thought processes that may be missed or
under-represented with the use of fewer metrics. The Montgomery-Åsberg Depression Rating
Scale was chosen as the primary tool for measurement of depression in this study because it
was originally designed for use by trained clinicians in rating depression severity in the
inpatient setting, matching the context of the proposed research environment. In order to
minimize bias, the research personnel who complete subject assessments taking place on Day 1
and 2 of the study, and during the follow-up visit will be blinded given that assessments on
these days involve the completion of examiner-rated scales (MADRS, CGI). Dr. Brueckner (PI)
or Dr. Tolliver (co-PI) will be the clinicians performing all screening, initial phase, and
follow-up assessments during the course of the study. Blinding will be maintained by the
Investigational Drug Service of Medical University of South Carolina (MUSC). Dosing of
Dextromethorphan will delivered as two 75mg doses separated by 4 hours. Because there is no
preliminary research involving the use of Dextromethorphan in the intended study population,
the choice of a total combined dose 150mg dosage represents a best-estimate extrapolation for
achieving an adequate pharmacologic effect, while maintaining subject safety. In a study
where dextromethorphan was used to investigate its analgesic properties in subjects with
Fibromyalgia, statistically significant pain reduction was achieved at a dose of 90mg, but
not 60mg. Pain reduction is likely mediated by effects of Dextromethorphan and its primary
metabolite Dextrophan on N-methyl-D-aspartate (NMDA) receptors. Adequate binding at this
receptor is specifically sought after in this study, as NMDA-receptor antagonism is also the
mechanism theorized to impart its potential as a rapid acting antidepressant (although sigma
receptor binding may be significantly important as well). Therefore, it is assumed that a
dose of at least 90mg is needed to achieve measurable NMDA-receptor activity, and therefore
an antidepressant response.
Although only certain concomitant medication regimens will be allowed during the course of
the trial as outlined in detail in the inclusion/exclusion criteria below, it should be noted
that subjects on certain antidepressant medications like Sertraline, Venlafaxine,
Escitalopram, and Bupropion (to name only a few) will be allowed participate in the trial.
As has been discussed so far, and in the following sections of this protocol, studies
involving the use of Dextromethorphan for neurological and psychiatric purposes have largely
used Dextromethorphan combined with Quinidine, now available as an FDA-approved treatment for
Pseudobulbar Affect as a medication called Nuedexta. The Quinidine component inhibits the
metabolism of Dextromethorphan, increasing duration of effect, Dextromethorphan plasma
levels, and reducing the formation of active metabolite Dextrophan. The decision was made to
use dextromethorphan alone in the study for several reasons. The first reason was to avoid
introducing undue cardiovascular risk to study participants. Quinidine is an antiarrhythmic
drug that can prolong QT interval (although this effect is usually minimal in doses used to
achieve inhibition of Dextromethorphan metabolism). Given that many psychiatric medications
can prolong QT interval, it was felt that it would be safer not to use Quinidine component
along with Dextromethorphan. Secondly, it was felt prudent to ensure that pharmacologic
action of Dextromethorphan was not unduly extended (through metabolism inhibition) to protect
against the development of protracted side-effects. Additionally, it is actually the primary
metabolite of Dextromethorphan, Dextrophan, which has the most robust NMDA receptor
antagonist properties. Because action at this receptor is specifically sought due to its
presumed antidepressant properties, development of this metabolite is desired, and would be
truncated by use of Quinidine or other inhibitors of Dextromethorphan metabolism (for
additional details about Dextromethorphan metabolism, and related considerations, see the
subsequent sections).
When a subject has undergone screening outlined in the procedural documentation herein and is
enrolled in the study, they will be given Dextromethorphan or placebo as two doses. In this
study, the investigators will be using Dextromethorphan Hydrobromide Monohydrate powder
supplied by the MUSC Investigational Drug Service that will be compounded as a single-capsule
preparation with dextrose filler. The placebo will also be provided by the MUSC
Investigational Drug Service and consist of dextrose in a single-capsule preparation.
Dextromethorphan or placebo will be administered both times with 8 ounces of water. The 75mg
dose of Dextromethorphan or the placebo will be administered twice, with the second dosing
occurrence taking place 4 hours after the first. In the event that the study subject were to
experience a serious adverse event with the initial dose, or be felt to be at risk for an
adverse outcome based on their response to the initial dose, they will not be eligible to
receive the second dose, and will be removed from the study. Additionally, if the study
subject does not want to receive a second dose at the 4 hour mark, their request will be
obliged. In the case that this occurs, the remainder of the assessments will occur as normal,
as if they did receive the second dose. There will be no requirements regarding food intake
or lack thereof before study drug administration on either dosing occasion. Because the
effects of a 75mg dose of Dextromethorphan may be subjectively detectable, subject blinding
may be compromised due to the presence of interoceptive cues. To detect the presence of this
potential issue, subjects participating in this study will be asked to which treatment group
they believe they have been assigned. Depression, anxiety, and mood metrics will be obtained
1 hour before dosing of study drug or placebo, at hour 2-4 after the initial dosing, at hour
6-8 hours (2-4 hours after the second dose is administered at the 4 hour mark), and the
following day, 24-36 hours after the initial dose. In order to ensure that subjects
participating in this study have very intensive follow-up, they will be required to engage in
an follow-up visit that will take place the Thursday or Friday following the initial phase of
the study, on an inpatient or outpatient basis depending on whether the study subject is
discharged from the hospital or not. The same standardized mood assessments will also be
obtained during this follow-up visit. During all of these described encounters, adverse
events will be recorded, and if necessary additional care will be rendered. The timing,
design, and layout of this study were in part extrapolated from a similar study using
single-dose intranasal ketamine to treat depression. The timing of measurements was adjusted
(compared to the referenced study) to accommodate the pharmacokinetics of Dextromethorphan,
enhance study feasibility in the proposed inpatient setting, and allow for 2 doses to be
administered to enhance drug exposure. For example, the first encounter with a subject will
take place 2-4 hours post-dosing (and 6-8 hours, which is 2-4 post second dosing), as peak
plasma levels of Dextromethorphan are usually achieved at this time. In addition to mood
metrics obtained during these encounters, during Day 1/Hour -1, Day 1 /Hour 2-4, Day 1/Hour
4, Day 1 /Hour 6-8, and Day 2 /Hour 24-36 the subject will undergo a physical and
neurological assessment to monitor for any evidence of untoward medication effect above and
beyond adverse events elicited from a verbal exchange with the study subject, based on
initial assessment gathered prior to study drug administration (Day 1/Hour -1). This
assessment is described below. In line with prior research involving the use of medications
with dissociative properties, the Clinician-Administered Dissociative States Scale will be
administered in an effort to capture any dissociative signs or symptoms exhibited or
experienced by the study subject.
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