Efficacy of Cranial Electrotherapy Stimulation (CES) for the Treatment of Major Depressive Disorder

A 6 week, randomized, double-blind, placebo controlled trial of the efficacy and tolerability
of Cranial Electrotherapy Stimulation for the treatment of Major Depressive Disorder, with a
2 week open label extension phase. This study will take place in Puerto Rico.

Inclusion Criteria:

Patients must be able to provide informed consent and sign the informed consent form prior
to the conduct of any study specific procedures. To be eligible to participate in the
study, patients must meet the following criteria:

1. Subject is a male or female outpatient age 18 (21 in Puerto Rico) to 65 years,
inclusive.

2. Subject meets DSM-5 criteria for MDD as determined by MINI screening interview.

3. The subject has a score of > 4 on CGI-S on visit 1 and 2.

4. Sexually active female patients of childbearing potential must be practicing at least
one or more the following methods of contraception during the study: intrauterine
device (IUD), barrier method in combination with a spermicide, oral/hormonal
contraception or abstinence. Female patients of childbearing potential must have a
negative pregnancy test prior to receiving study treatment.

5. Subject is in good medical health or with chronic medical conditions which are
currently stable.

6. No current abuse of alcohol or other substance.

7. Capable of doing active or sham CES treatments and completing all study requirements
independently.

8. The subject has a score of ≥ 17 on the HAM-D. If a subject is being treated with
Serotonin Selective Reuptake Inhibitor (SSRIs) medications which include: Fluoxetine
(Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Luvox (Fluvoxamine), Citalopram
(Celexa) and Escitalopram (Lexapro), as well as serotonin and norepinephrine reuptake
inhibitors (SNRI) such as Venlafaxine (Effexor IR and XR), Desvenlafaxine (Pristiq)
and Duloxetine (Cymbalta) they may remain on one of the SSRI or SNRI medications
provided that he or she has been on a stable dose for at least 4 weeks prior to
entering this study; this dose is to remain stable throughout the remainder of this
study (any need to change the dose during the study will be evaluated and will result
in termination).

Exclusion Criteria:

Patients will be not be considered for inclusion into the study if they meet any of the
conditions below:

1. Subject meets DSM-5 criteria for another axis 1 disorder (other than MDD) as the
primary diagnosis (i.e., schizophrenia, mood disorder, psychosis, anorexia nervosa) as
determined by the MINI. Conduct and antisocial personality disorders will not be
allowed to participate. Patients with comorbid diagnoses of learning disorders,
attention deficit disorder (with or without hyperactivity), communication disorders,
separation anxiety disorder, dysthymic disorder or anxiety disorders will be allowed
to participate in the study as long as these conditions are not the primary focus of
any treatment and they comply with concomitant medication limitations listed in the
appendix. Those with substance use disorders will not be allowed to participate.

2. Subject is clinically judged by the investigator to be at risk for suicide or is
acutely suicidal as objectively measured by the C-SSRS.

3. Subject has attempted suicide one or more times within the past 12 months

4. Subject has a Hamilton Depression Rating Scale17 (HAM-D17) score above 38 which
suggests a moderate to severe clinical level of depressive symptoms

5. Subject has a psychiatric condition that would require inpatient, or partial
psychiatric hospitalization.

6. There is an imminent risk of injuring self or others or causing damage to property as
judged by the investigator.

7. Subject has a significant history of medical disease (i.e., cardiovascular, hepatic
(e.g., cirrhosis, hepatitis B or C) renal, gynecological, musculoskeletal,
neurological, gastrointestinal, metabolic, hematological, endocrine, cancer with a
metastatic potential, progressive neurological disorders or seizure disorder) which
could impair reliable participation in the trial or necessitate the use of medication
not allowed by this protocol unless all of the following are true (consultation with
study physician is encouraged before patient enrollment):

1. The condition has been stable for over one year (3 years for malignancy other
than excised basal cell carcinoma, for which one year stability is required).

2. The condition has been judged by the Investigator not to interfere with the
patient's participation in the study.

3. The condition is fully documented in the patient's study records.

8. Hypo- or hyperthyroidism, unless stabilized on appropriate pharmacotherapy with no
change in dosage for at least three months before visit 1 (Screening).

9. Subject is pregnant, planning to become pregnant, or nursing. If a subject becomes
pregnant, she will be discontinued immediately and followed appropriately.

10. For females who are sexually active:

Not practicing a reliable method of contraception that will continue for the duration
of the study and within 30 days following the end of study participation.

Reliable contraception is defined as:

1. surgical sterilization

2. oral contraceptives (consisting of an estrogen-progestin combination or progestin
alone

3. transdermally derived contraceptives (e.g., Ortho - Evra), depot injections
(e.g., Depo-Provera)

4. vagina contraceptive ring (e.g., Nucaring), contraceptive implants (e.g.,
Implanon, Norplant 2/Jadelle)

5. an intrauterine device

6. diaphragm plus condom (the only acceptable double barrier method)

7. other forms of contraceptives (pharmacological and/or non-pharmacological) are
not accepted

11. Subject has had concomitant therapy with another investigational drug, or
participation in an investigational drug study within one month prior to entering this
study.

12. Subject who has initiated or terminated psychotherapy or behavior therapy within one
month before visit 1 (screening), or who plans to initiate or change such therapy
during the course of the study.

13. Subject has history of poor compliance or in the Investigator's opinion any subject
whose treatment as an outpatient would be clinically contraindicated.

14. Subject has had previous trial of cranial electrotherapy stimulation (CES).

15. Subject requiring prohibited concomitant medication or herbal supplements that could
not be discontinued or switched to an allowable alternative medication and stabilized
for at least two weeks preceding (visit 2).

16. Subject taking any psychoactive drug or herbal remedy within 5 half-lives before
baseline (visit 2), (St. John's wort, ginkgo biloba, kava kava, valerian root, DHEA,
tyrosine, tryptophan and 5-HTP, antidepressants, anxiolytics, monoamine oxidase
inhibitors, antipsychotics, or anticonvulsants/mood stabilizers, carbamazepine, or
others). Patients who have ever been treated with the depot antipsychotic must also be
excluded.