An Open Label Trial of TMS Therapy for Bipolar Depression

The investigators propose to screen patients with bipolar depression I or II, who are already
on acceptable mood stabilization. They may or may not be on antidepressants at the time of
screening but subjects on antidepressants would be taken off them before completing the
screening phase. Those patients who have a depression of at least moderate severity without
significant symptoms of activation or mania will be started on a course of open label TMS
treatment of up to 35 sessions. Safety and efficacy assessments will be done weekly. Patients
will complete a course of treatment when they meet remission criteria (MADRS score < 10) or
at the end of 30 treatments, whichever comes first. Patient who are still judged to be
improving between treatment 25 and treatment 30 will be eligible to complete up to five
addition treatments as the discretion of each site's principal investigator. Patients who
meet response criteria (MADRS score decreases by at least 50%) will complete the full course
of 30 to 35 TMS sessions. Patients will be withdrawn for safety concerns, particularly the
onset of activation suggestive of mania or a mixed state.

Patients who meet response or remission criteria will be followed monthly for up to six
months to evaluate the durability of response. They will be on standard mood stabilizing
medications and psychotherapy per their clinician's discretion.

Inclusion Criteria- Phase II:

1. Must be at least 18 years old.

2. Must meet DSM-5 criteria for bipolar (either I or II) depression by clinical interview
and M.I.N.I. The duration of the current depressive episode must be at least 4 weeks
and no longer than 3 years in length.

3. Should have a MADRS score of at least 20 at screening, an YMRS score of less than 12
and a CGI score of at least 4.

4. Must have signed the informed consent document and have a level of understanding
sufficient to provide informed consent and to communicate with the investigator and
site personnel.

5. Must be on a mood stabilizer acceptable to the study physician which is consistent
with their diagnosis. The mood stabilizer must be at a stable dose for at least four
days before starting TMS treatment.

6. If female of childbearing potential, patients must

1. have a negative urine pregnancy test at screening, and

2. not be nursing or planning a pregnancy, and

3. be on a medically acceptable method of birth control acceptable to the principal
investigator.

Choices of contraception that meet the study requirements are

- Intrauterine device

- Hormonal contraception (estrogen-containing birth control pills, Vaginal ring, patch,
injections or implants)

- Latex condom with spermicide

- Diaphragm with spermicide

- Cervical cap with spermicide

Females of childbearing potential who are abstinent can enroll in the study.

Exclusion Criteria- Phase II:

1. May not be directly affiliated with Sheppard Pratt Clinical Research Programs or be
immediate family of Research Programs personnel.

2. Must not have another primary Axis I diagnosis.

3. The subject must not have stopped an antidepressant less than two weeks before
starting TMS treatment or unable to discontinue antidepressant therapy.

4. Should have no previous history of psychosis or substance dependence or abuse within
the six months prior to Screening

5. Presence of an Axis II disorder felt by the investigator to potentially interfere with
study compliance would exclude a potential participant.

6. Should not have prior intolerance of TMS or significant lack of response to adequate
trials of TMS.

7. Should not have a lifetime history of lack of response to ECT or VNS.

8. Should not have any medical condition likely to interfere with safe study
participation.

9. Women of child-bearing potential who are not using a medically accepted means of
contraception when engaging in sexual intercourse are excluded, as well as women who
are pregnant or breast-feeding.

10. Positive urine screen for any substance of abuse will exclude a patient, with the
exception of benzodiazepines. A satisfactory explanation in the opinion of the
investigator along with a negative repeat screen prior to Visit 2 is possibly
acceptable.

11. Current suicide risk, as evidenced:

1. It is the judgment of the investigator that the patient may be at risk for
suicide

2. The patient has rated a "yes" to question 4 or question 5 on the Screening C-SSRS

3. The patient has attempted suicide within the past 12 months prior to Screening.

12. History of head injury, epilepsy or seizure disorder, non-removable metallic implants
or objects in or around the head.

Inclusion Criteria- Phase III Patients who meet MADRS criteria for response or remission
will enter Phase III, the six month follow-up phase of the study.