Synchronized Transcranial Magnetic Stimulation (sTMS) in Major Depressive Disorder

Major Depressive Disorder (MDD) is a mental disorder associated with significant functional
impairment and disability. Affected individuals present with depressed mood, loss of
interest or pleasure, feelings of guilt, low self-worth, disturbed sleep or appetite, low
energy, and poor concentration.

Psychopharmacological therapy as today's mainstream treatment has revolutionized the
clinical management for major depressive disorders and has been shown to improve the quality
of life for many patients. With that, these therapies are not effective for all patients.
Results released from the Sequenced Treatment Alternatives to Relieve Depression Study
(STAR*D), conducted by the National Institute of Mental Health (NIMH), show that
approximately 30% of depressed subjects respond to an SSRI in their first trial, despite
adequate dosing and duration of treatment. The SSRI antidepressants do have a more favorable
side effect profile than older medications, but they still may be difficult for some
patients to tolerate because of gastrointestinal distress, anxiety, insomnia, and sexual
dysfunction.

In addition to the psychopharmacologic treatments for depression, other therapies such as
electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) have
been shown to have a therapeutic effect in MDD. ECT induces seizures electrically in
anesthetized subjects. It is generally safe and effective; however the procedure can have
the negative side effect of memory loss and confusion. Treatment with repetitive stimulation
(rTMS) is intended to stimulate groups of cells in areas of the brain linked to MDD. While
the therapy is non-invasive, it is expensive, involves a complex method for locating the
point of stimulation in the brain, and has the potential for seizures.

rTMS uses magnetic pulses which causes neuronal activation of specific areas in the brain.
It is generally believed that this activation causes resetting of cortical oscillators to
create a therapeutic effect in MDD. The investigators hypothesize that TMS using low energy,
sinusoidal magnetic fields synchronized to a patient's individual alpha frequency,(sTMS),
can also affect neuronal activity leading to a reemergence of intrinsic rhythms and clinical
improvement in MDD. Preliminary study results using sTMS have shown improvements in
depressive symptoms with minimal side effects.

This multicenter study is designed to evaluate the safety and efficacy of sTMS in subjects
with Major Depressive Disorder. Subjects will be randomized to receive treatment 5 days per
week for 6 weeks. At the end of Treatment Week 6, subject will have completed the study
treatments and will be offered open label sTMS therapy or alternate antidepressant treatment
as clinically indicated. At minimum, subjects will be asked to return for one follow-up
visit four weeks after their last double-blind treatment (Week 10) for evaluation and study
completion.

Inclusion Criteria:

- Subjects will meet the DSM-IV-TR primary diagnosis of initial or recurrent Major
Depressive Disorder by DSM-IV-TR criteria rendered by structured interview using the
Mini International Neuropsychiatric Interview (MINI).

- HAM-D17 score >= 17 and Item 1 score greater than or equal to 2.

- Duration of current episode >=8 weeks. The definition of an episode is demarcated by
a period of >=2 months when the subject did not meet full criteria for the DSM-IV-TR
definition of Major Depressive Episode. Maximum duration of current episode cannot
exceed 2 years.

- The baseline EEG is of sufficient duration and quality that it can be processed for
quantitative analysis.

- Subjects are willing and able to adhere to the intensive treatment schedule and all
required study visits.

Exclusion Criteria:

- Subjects are unable or unwilling to give informed consent.

- Diagnosed with the following conditions (current unless otherwise stated):

- Any other current primary Axis I mood, anxiety, or psychotic disorder, including
bipolar disorder.

- Depression secondary to a general medical condition, or substance-induced.

- History of substance abuse or dependence within the past 6 months (except
nicotine and caffeine).

- Any bipolar disorder or psychotic disorder (lifetime), including schizoaffective
disorder, or major depression with psychotic features in this or previous
episodes.

- Eating disorder (current or within the past year).

- Obsessive compulsive disorder (lifetime).

- Post-traumatic stress disorder (current or within the past year).

- ADHD (currently being treated).

- Subjects meeting criteria for Axis II cluster A or B diagnosis based upon DSM-IV TR
criteria, which in the judgment of the Investigator may hinder the subjects in
completing the procedures required by the study protocol.

- Subjects with a clinically defined neurological disorder including, but not limited
to:

- Any condition likely to be associated with increased intracranial pressure.

- Space occupying brain lesion.

- Any history of seizure EXCEPT those therapeutically induced by ECT (childhood
febrile seizures are acceptable and these subjects may be included in the
study).

- History of stroke.

- Transient ischemic attack within two years.

- Cerebral aneurysm.

- Dementia.

- Mini Mental Status Exam (MMSE-2) score of =<24.

- Parkinson's disease.

- Huntington's disease.

- Multiple sclerosis.

- Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), or currently
taking medication that lowers the seizure threshold. Medications that lower the
seizure threshold are included in the Prohibited Concomitant Medication (Section
5.7).

- Subjects who are currently hospitalized due to severity of depression symptoms.

- Subjects with any of the following treatment histories:

- TMS treatment within 6 months prior to the screening visit.

- ECT treatment within 1 year prior to the screening visit.

- Failure to respond to TMS or ECT treatment (i.e., consistent with ATHF
confidence level 3 or higher) in this or any previous episode.

- Lifetime history of treatment with Deep Brain Stimulation or Vagus Nerve
Stimulation.

- Use of any investigational drug or device within 4 weeks of the randomization
visit.

- Subjects who have been treated with fluoxetine within the past four weeks.

- If participating in psychotherapy, must have been in stable treatment for at
least 2 months prior to entry into the study, with no anticipation of change in
the frequency of therapeutic sessions, or the therapeutic focus over the
duration of the trial.

- Failure to respond to Monoamine Oxidase Inhibitors (MAOIs) in the current
episode.

- Use of any medication(s) listed on the Prohibited Concomitant Medication within 1
week of randomization.

- Subjects are adequately benefiting from current antidepressant medication(s).

- Significant acute suicide risk, defined as:

- Suicide attempt within the previous 6 months that required medical treatment; or

- Greater than or equal to 1 suicide attempts in the past 12 months; or

- Has a clear-cut plan for suicide and states that he/she cannot guarantee that
he/she will call his/her regular psychiatrist or the Investigator if the impulse
to implement the plan becomes substantial during the study; or

- In the Investigator's opinion, is likely to attempt suicide within the next 6
months.

- Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute,
unstable cardiac disease.

- Intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants,
stents, or electrodes) or any other metal object within or near the head, excluding
the mouth, which cannot be safely removed.

- Clinically significant abnormality or clinically significant unstable medical
condition, as indicated by medical history, physical examination, ECG results, or
clinical laboratory testing, that in the Investigator's judgment might pose a
potential safety risk to the subject or limit interpretation of the trial results,
e.g., any uncontrolled thyroid disorders, hepatic, cardiac, pulmonary and renal
malfunctioning.

- Women who are currently pregnant or not using a medically acceptable means of birth
control and women who are breastfeeding.

- Positive urine drug screen for illicit substances. (A positive urine drug screen at
screening may be repeated once prior to randomization).

- Any condition which in the judgment of the Investigator would prevent the subject
from completion of the study.