Nuedexta in Treatment-Resistant Major Depression

Approximately one-third of patients with major depressive disorder do not achieve adequate
symptom control despite a series of multiple treatment trials with currently available
antidepressant medication (for example a serotonin-selective reuptake inhibitor). This group
of patients - representing treatment-resistant depression (TRD) - accounts for an alarmingly
high public health burden and signifies a critical area of need in pharmaceutical treatment
development. While current treatments are slow to act and only partially effective, new basic
and clinical research focusing on the glutamate system is yielding promising new avenues for
novel drug discovery. Ketamine - a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist
- has now been demonstrated in several studies to bring about a rapid and robust
antidepressant effect, even in patients suffering from TRD. Ketamine is limited as a
treatment for TRD by the need for intravenous administration and the potential for untoward
medical or psychiatric adverse effects. There is an urgent need, therefore, to identify
well-tolerated, orally available compounds that target the NMDA receptor as a novel treatment
approach for TRD. The current project aims to test the safety, tolerability and efficacy of
Nuedexta - containing the NMDA antagonist dextromethorphan.

Inclusion Criteria:

- Male or female participants, 18-65 years of age;

- Current primary Axis I diagnosis of major depressive disorder according to DSM-IV-TR
criteria as determined by a psychiatrist and confirmed with the Structured Clinical
Interview for DSM-IV Axis I Disorders (SCID);

- Current treatment-resistant depression defined by a history of inadequate response to
a minimum of 2 adequate antidepressant treatment trials determined by patient history
and chart review and confirmed with the Antidepressant Treatment History Form (ATHF);

- Participants must be willing to discontinue treatment with concomitant medications
that are disallowed by the study protocol;

- Participants must have a level of understanding of the English language sufficient to
agree to all tests and examinations required by the study and must be able to
participate fully in the informed consent process.

Exclusion Criteria:

- Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder,
pervasive developmental disorders or mental retardation

- Diagnosis of a substance use disorder within the past 1 year ;

- Female participants who are pregnant, nursing, for may become pregnant;

- Any unstable medical illnesses including hepatic, renal, gastroenterologic,
respiratory, cardiovascular (including ischemic heart disease); endocrinologic,
neurologic (including history of severe head injury), immunologic, or hematologic
disease;

- Participants with clinically significant abnormalities of laboratories, physical
examination, or ECG;

- Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de
pointes, or heart failure;

- Complete atrioventricular (AV) block without implanted pacemaker, or patients at high
risk of complete AV block

- Participants with a history of quinidine, quinine or mefloquine-induced
thrombocytopenia, hepatitis, or other hypersensitivity reactions;

- Participants judged to be at serious suicidal risk by the PI;

- Concomitant use with quinidine, quinine, or mefloquine;

- Participants with known hypersensitivity to dextromethorphan;

- Use with an MAOI or within 14 days of stopping an MAOI;

- Concomitant use with drugs that prolong QT interval and are metabolized by CYP2D6