A Paroxetine- and Placebo-Controlled Study of 50 mg/Day and 100 mg/Day of EB-1010 Among Outpatients With Major Depressive Disorder Who Have Responded Inadequately to Prior Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Inclusion Criteria:

- Patients must be able to give informed consent, (as required by IRB/IEC), prior to
the initiation of any protocol required procedures.

- Patients must be able to understand the nature of the study, agree to comply with the
prescribed dosage regimens, report for regularly scheduled office visits, and
communicate to study personnel about adverse events and concomitant medication use.

- Patients with a diagnosis of major depressive episode as defined by DSM-IV-TR
criteria, based on the SCID-CT29; their major depressive episode must be deemed
"valid" using the SAFER criteria interview24 administered by remote, independent
raters.

- Patients who have reported a history for the current depressive episode of an
inadequate response to 1 and no more than 1 adequate SSRI or SNRI treatment. An
inadequate response is defined as less than a 50% reduction in depressive symptom
severity, as assessed by the MGH ATRQ administered by remote, independent raters. An
adequate trial is defined as an antidepressant treatment for at least 8 weeks
duration at least at the minimum dose as specified in the MGH ATRQ.

- Patients must have a 17-item Hamilton Rating Scale for Depression (HAM-D-17) (whose
score is derived from the HAM-D-28)20 score ≥ 18 during the screening phase to
qualify for inclusion. The HAM-D-28 will be administered by the study clinicians at
the screening and baseline visits, and by remote, independent raters during the
screening phase at the time of the SAFER interview.

- Patients must have a Body Mass Index (BMI) of approximately 18-40.

- Patients must be able to be reliably rated on the psychiatric scales required by the
protocol based on Investigator's judgment.

- Patients must be able to understand and read English.

- Placebo non-responders are defined as those patients who failed to achieve at least a
50% decrease in their MADRS score at visit 8 (Week 6), AND have a MADRS score of = or
> 16 at visit 8 (Week 6)

- Men and women, ages 18 to 65 inclusive.

- Meet DSM-IV-TR criteria (by Structured Clinical Interview for DSM-IV-TR - SCID-CT)
for MDD, current.

- Treated with one of the allowed SSRIs or SNRIs at adequate doses (defined as 20mg/day
or more of citalopram; 10 mg/day or more of escitalopram, 50mg/day or more of
sertraline; 125 mg/day or more of venlafaxine; 60 mg/day or more of duloxetine)
during the current episode for at least 8 weeks, with the same, adequate dose over
the last 4 weeks.

- Between the screen and baseline visits, patients must be documented to have less than
a 25% reduction in QIDS-SR score.

- Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks after the
last dose of investigational product in such a manner that the risk of pregnancy is
minimized. Adequate methods are defined as those which result in a low failure rate
(i.e., less than 1% per year) when used consistently and correctly such as implants,
injectable or patch hormonal contraception, oral contraceptives, an IUD,
double-barrier contraception, sexual abstinence. Form of birth control will be
documented at screening and baseline.

WOCBP include any female who has experienced menarche and who has not undergone successful
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
or is not postmenopausal (defined as amenorrhea ³ 12 consecutive months); or women on
hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH]
level > 35 mIU/mL). Even women who are using oral contraceptives, other hormonal
contraceptives (vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is
sterile (e.g., vasectomy) should be considered to be of childbearing potential. WOCBP must
have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of
HCG) within 72 hours prior to the start of investigational product.

Exclusion Criteria:

- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for
the entire study period [and for up to 4 weeks after the last dose of investigational
product.

- WOCBP using a prohibited contraceptive method that does not meet established and
acceptable medical standards.

- Women who are pregnant or breastfeeding.

- Women with a positive pregnancy test on enrollment or prior to investigational
product administration.

- Sexually active fertile men not using effective birth control if their partners are
WOCBP.

- Patients who do not report any prior inadequate response (equal or greater than 50%
decrease in depressive symptom severity) or report an inadequate response (less than
50% decrease in depressive symptom severity) to more than 1 prior adequate trials of
antidepressant treatments during the current depressive episode (including
monotherapy treatment and distinct combination regimens) at a therapeutic dose (as
defined by the MGH ATRQ)22-23 and for an adequate duration (minimum 6 weeks for any
monotherapy).

- Patients who report treatment with adjunctive medication (buspirone, atypical
antipsychotics, lithium) to their antidepressant therapy for a minimum of 4 weeks
during the current depressive episode.

- Patients with a current need for involuntary commitment or who have been hospitalized
within 4 weeks of the Screening Visit for the current major depressive episode.

- Subjects with other DSM-IV-TR Axis I disorders other than Generalized Anxiety
Disorder (GAD: 300.02), Social Anxiety Disorder (300.23), or Specific Phobia
(300.29). Subjects with co-morbid GAD, Social Anxiety Disorder, or Specific Phobia
are ineligible if the co-morbid condition is clinically unstable, requires treatment,
or has been the primary focus of treatment within the 6 month period prior to
screening. More specifically, patients who have a current Axis I diagnosis

- Patients experiencing hallucinations, delusions, or any psychotic symptomatology in
the current or any previous depressive episode.

- Patients who have met DSM-IV-TR criteria for any significant substance use disorder
within the past six months, based on the SCID-CT.

- Patients receiving new-onset psychotherapy and/or somatic therapy (light therapy,
trans-cranial magnetic stimulation) within 6 weeks of screening, or at any time
during participation in the trial.

- Patients who, in the opinion of the Investigator, are actively suicidal and at
significant risk for suicide.

- Patients who have participated in any clinical trial with an investigational drug or
device within the past month.

- Patients who routinely perform shift work and whose sleep-wake cycle is frequently
changed because of their work.

- Patients who have received ECT in the past 20 years or Vagal Nerve/Deep Brain
Stimulation during their lifetime.

- Unstable medical illness including, cardiovascular, hepatic, renal, respiratory,
endocrine, neurological, or hematological disease.

- Subjects with evidence or history of significant neurological disorder, including
head trauma with loss of consciousness, history of stroke, Parkinson's disease,
epilepsy disorder, conditions that lower seizure threshold, seizures of any etiology
(including substance or drug withdrawal), who are taking medications to control
seizures, or who have increased risk of seizures as evidenced by history of EEG with
epileptiform activity (with the exception of juvenile febrile seizures).

- Subjects who are known to have AIDS or to be HIV positive.

- Patients with a significant history of drug or food allergy or hypersensitivity.
Specifically, patients who report a history of drug-induced and/or food-induced
asthma, facial-swelling, tongue swelling, angioedema, urticaria, stridor, hives,
epiglottis swelling, recurrent skin rashes, toxic epidermal necrolysis, or
Stevens-Johnson Syndrome.

- Patients who, in the Investigator's judgment represent a significant risk of
committing suicide during the course of the trial based on history or evaluation of
current mental status. Patients with significant hostility and history of aggressive
acts who, in the Investigator's judgment, represent a significant risk of committing
violent acts during the course of the trial based on history or evaluation of current
mental status.

- Patients who have a history or evidence of a medical condition that would expose them
to an undue risk of a significant adverse event or interfere with assessments of
safety or efficacy during the course of the trial.

- Patients with thyroid pathology (unless condition has been stabilized with
medications for at least the past three months).

- Patients with a lifetime history of serotonin syndrome.

- Patients with a significant history of a seizure disorder.

- Patients who have received a vaccination in the past three months.

- Patients with a recent (within two weeks) viral or systemic illness.

- Patients with current skin rashes.

- Patients who have recently (within two weeks) begun any medications.

- Patients who have a positive urine drug screen which cannot be explained by
prescribed medications.

- Patients with AST and/or ALT >2x ULN at the screening visit.

- Patients with abnormal thyroid-stimulating hormone (TSH) concentrations or positive
hepatitis tests.

- Patients with clinically significant laboratory abnormalities (hematology, chemistry,
urinalysis) or with Safety Values of Potential Clinical Concern (see Table 3).

- Diastolic blood pressure > 105 mmHg at screen or baseline.

- Any signs or symptoms that are, in the Investigator's judgment, medically
significant, in that they would impact the patient's safety.

- Patients with a QTc value of 460 ms or greater.

- Patients who are known to be allergic or hypersensitive to paroxetine and EB-1010.

- Patients previously treated with and not responding to paroxetine

- Monoamine oxidase inhibitors (e.g., Nardil, phenelzine, Parnate, tranylcypromine,
Marplan, isocarboxazide) treatment within the 2 weeks prior to enrollment.

- Patients who would likely require prohibited concomitant medications and/or other
depression treatment during the trial.

- Prisoners or subjects who are involuntarily incarcerated.

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness.

- Patients who demonstrate a 25% or greater decrease in depressive symptoms as
reflected by the QIDS-SR19 total score from screen visit to baseline visit.

- Patients who plan to have elective surgeries during the course of the study.

- Patients with a history of antidepressant-induced hypomania or dysphoria.

- Patients who demonstrate a less than 80% compliance (as measured by pill count) of
their antidepressant medication during the Screening Phase.