Overview

The purpose of this trial is to determine if intermittent theta-burst stimulation (iTBS) can reduce the symptoms of depression in treatment-resistant bipolar disorder. To do this, some of the participants in this study will receive treatment with active iTBS stimulation, while others will receive sham iTBS stimulation. Participants will come for 30 days of either active iTBS or sham iTBS, with a 6-week follow-up period. Symptoms of depression (for determining treatment efficacy) and mania (for determining treatment safety) will be assessed using the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Young Mania Rating Scale (YMRS) every five treatments during the treatment course, and at 1 week and 6 week after treatment completion.

Eligibility

Inclusion Criteria:

        The participant must meet all of the inclusion criteria to eligible for this clinical
        trial:
          1. Must be deemed to have capacity to provide informed consent;
          2. Must be an outpatient;
          3. Have a DSM 5 diagnosis of bipolar disorder (type I or II), current episode depressed
             confirmed by Mini-International Neuropsychiatric Interview version 7.0.2 (MINI);
          4. Age 18-65;
          5. failure to achieve a clinical response to ≥1 adequate treatment trial for bipolar
             depression based on the Antidepressant Treatment History Form - Short Form (ATHF-SF)
             OR unable to tolerate at least 2 separate inadequate treatment trials;
          6. moderately severe depression with a score ≥ 15 on the PHQ-9;
          7. not currently experiencing a mixed or manic episode (YMRS ≤10);
          8. no increase or initiation of psychotropic medication with intention of treating
             depressive symptoms in the 4 weeks prior to screening. This excludes targeted
             treatment of insomnia with trazodone, melatonin, low-dose doxepin [3-6mg], low-dose
             benzodiazepines [≤2mg lorazepam daily equivalent], non-benzodiazepine benzodiazepine
             receptor agonists, or orexin antagonists;
          9. currently receiving treatment with one of the following non-anticonvulsant mood
             stabilizer with evidence for prevention of mania: lithium, quetiapine, asenapine,
             aripiprazole, paliperidone (>6mg), risperidone, olanzapine, ziprasidone,
             haloperidol, clozapine (lurasidone and cariprazine are excluded due to lack of
             evidence for preventing mania);
         10. able to adhere to the treatment schedule;
         11. pass the TMS adult safety screening questionnaire.
        Exclusion Criteria:
        An individual who meets any of the following criteria will be excluded from participation
        in this clinical trial:
          1. have a history of MINI diagnosis of a substance use disorder (other than nicotine
             and/or caffeine) within the last 3 months;
          2. have a concomitant major unstable medical illness;
          3. have active suicidal intent (assessed during HRSD-17 Item 3 and SSRS as imminent
             intent to act on specific plan, confirmed by psychiatric staff);
          4. are pregnant or intend to get pregnant during the study;
          5. have a lifetime MINI diagnosis of schizophrenia or schizoaffective disorder;
          6. have psychotic symptoms within the current episode;
          7. have a MINI anxiety disorder, trauma-related disorder, obsessive compulsive disorder,
             or personality disorder assessed by a study investigator to be primary and/or causing
             greater impairment than BD-DE;
          8. failure of an adequate acute course of ECT as defined by ATHF-SF during the current
             episode;
          9. have received any rTMS before due to potential to compromise blinding of treatment
             allocation;
         10. have any clinically significant neurological disorder (e.g., recent major
             cerebrovascular accident), or any history of seizure except those therapeutically
             induced by ECT or with clear precipitant (e.g., febrile seizure of childhood, alcohol
             withdrawal, etc.);
         11. have any intracranial implant (e.g., aneurysm clips, shunts, stimulators,) or any
             other metal object within or near the head, excluding the mouth, that cannot be safely
             removed;
         12. are participating in psychotherapy for less than 3 months. Patients will be permitted
             if they have been in stable treatment for at least 3 months prior to study entry, with
             no anticipated change in the frequency of therapeutic sessions, or focus of
             therapeutic sessions over the duration of the study;
         13. are currently taking lorazepam >2 mg daily (or equivalent) due to the
             potential to limit rTMS efficacy;
         14. are currently taking any dose of an anticonvulsant due to the potential to limit rTMS
             efficacy. If anticonvulsants have been discontinued prior to screening, at least 5
             half-lives have elapsed until screening to allow sufficient drug clearance;
         15. have a non-correctable clinically significant sensory impairment (i.e., cannot hear
             well enough to cooperate with interview).