Low-frequency rTMS to the right dorsolateral prefrontal cortex for bipolar depression

Low Frequency Right Dorsolateral Pre Frontal Cortical Repetitive TMS for Bipolar Depression

This trial will test whether once-daily low-frequency rTMS to the right DLPFC helps adults with treatment-resistant bipolar depression who did not improve after left-sided iTBS or sham.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 80 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Centre for Addiction and Mental Health (Academic / other)
• Locations: 2 sites (Toronto, Ontario and 1 other locations)
• Trial ID: NCT06986460 on ClinicalTrials.gov

What this trial studies

This Phase 3, interventional study delivers once-daily low-frequency repetitive transcranial magnetic stimulation (LFR rTMS) to the right dorsolateral prefrontal cortex for 30 treatment days using a MagPro X100/R30 stimulator with a Cool-B70 coil. Eligible participants are adults with DSM-5 bipolar I or II currently depressed, who failed to achieve response in a prior TRIBE protocol and meet symptom thresholds (PHQ-9 ≥10, YMRS ≤10). Depression (HRSD-17) and mania (YMRS) are monitored every five treatments and at 1 and 6 weeks after treatment to measure efficacy and safety. The trial is conducted at major Toronto centers with structured follow-up and safety monitoring for mood switching.

Who should consider this trial

Good fit: Adults (over 18) with DSM-5 bipolar I or II in a current depressive episode who are outpatients, have capacity to consent, failed to respond (≤50% HRSD-17 improvement) in the prior TRIBE protocol, have PHQ-9 ≥10 at screening and TRIBE follow-up, are within 3 months of TRIBE completion, and are not currently manic or mixed (YMRS ≤10).

Not a fit: People who are currently manic or mixed, who have recent medication changes intended to treat depression, or who are outside the eligibility window after the prior TRIBE participation are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this could provide a new noninvasive treatment option to reduce depressive symptoms in people with treatment-resistant bipolar depression.

How similar studies have performed: Low-frequency right-sided rTMS has shown benefit in some major depressive disorder studies, but its use specifically for treatment-resistant bipolar depression after left-sided iTBS is less well established and remains limited.

Eligibility criteria

Inclusion Criteria:

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) assessed during TRIBE trial participation with no contradictory evidence that the current episode is depressed from FLARE trial screening assessments (YMRS\>10/PHQ-9 \<10);
4. older than 18 years;
5. failure to achieve a clinical response within the TRIBE study (CTO#: 4343) defined as ≤50% response from baseline to 6 weeks on the HRSD-17.
6. Score ≥10 on PHQ-9 at both (i) the 6 weeks follow-up in the TRIBE trial and (ii) at screening;
7. ≤3 months from completion of the TRIBE study;
8. not currently experiencing a mixed or manic episode (YMRS ≤10);
9. 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;
10. 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);
11. able to adhere to the treatment schedule;
12. pass the TMS adult safety screening questionnaire.

Exclusion Criteria:

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;
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 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.);
10. 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;
11. if participating in psychotherapy, must have been in stable treatment for at least 3 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 study;
12. have a clinically significant laboratory abnormality, in the opinion of the one of the principal investigators;
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;
15. if anticonvulsants have been discontinued prior to screening, at least 5 half-lives have elapsed until screening to allow sufficient drug clearance;
16. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).
17. participant was withdrawn from the TRIBE study due to safety concerns or at the discretion of the PI.
18. any history of substance use in the last 4 weeks which poses a safety concern to undergo rTMS as assessed by the PI's review of responses to the trial's 'Substance Use Screening Questions Form'.

Where this trial is running

Toronto, Ontario and 1 other locations

• University Health Network Toronto Western Hospital — Toronto, Ontario, Canada (Recruiting)
• Centre For Addiction and Mental Health (CAMH) — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: Tyler Kaster — Camh
• Study coordinator: Elizabeth Clancy

Conditions Bipolar Depression Depressed Phase; rTMS; Bipolar Depression; treatment-resistant; LFR