A Trial of Dextromethorphan for Treatment of Major Depressive Disorder
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      A proof-of-concept study to determine the antidepressant potential of Dextromethorphan for
      treating depression associated with Major Depressive Disorder in inpatients.
    

Detailed description: 
      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.
    

Intervention name(s): Dextromethorphan Hydrobromide
Intervention type(s): Drug
Intervention description(s): Dose as a single capsule preparation formulated by the Investigational Drug Service of MUSC specifically for the purposes of this trial.
Intervention MeSH terms: Dextromethorphan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment