Treatment-resistant bipolar depression, i.e. patients with bipolar depression who did not respond to two or more adequately dosed medication trials Mental and Behavioural Disorders Bipolar affective disorder
Conditions
Interventions
Active repetitive transcranial magnetic stimulation (rTMS, low frequent 1Hz rTMS, targeting the right right dorsolateral prefrontal cortex), compared to sham rTMS.
In Phase 1, participants will be as
Sponsors
Amsterdam UMC Location VUmc
Eligibility
Sex/Gender
All
Age
18 Years to 110 Years
Inclusion criteria
Inclusion criteria: 1. 18 years of age or older 2. Sufficient level of spoken and written Dutch 3. Ability to freely provide written informed consent 4. Current DSM-5 diagnosis of a depressive episode in bipolar I or II disorder, ascertained by the Mini International Neuropsychiatry Interview (MINI-plus) 5. A Hamilton depression rating score (HDRS) of >16 points: this score will be obtained from the SIGH-ADS, a depression rating scale able to determine the HDRS score and a score for atypical depression 6. Have a medication-resistant bipolar depression, defined according to the criteria of Hidalgo-Mazzei, that is, lack of remission for 8 consecutive weeks after two different medication trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination 7. Stable medication 4 weeks prior to the study, including anti-manic medication, consisting of lithium, valproate, carbamazepine and all anti-psychotic drugs, in patients with bipolar I disorder. Dosages of anti-manic medications will be determined between the participant/patient and his/her psychiatrist. Stable medication also includes stable use of benzodiazepines up to a dosage equivalent of 3.0 mg lorazepam
Exclusion criteria
Exclusion criteria: 1. A (hypo)manic episode within 3 months before the start of the trial 2. A Young Mania Rating Scale score >12, before the start of the trial 3. Current psychotic disorder including psychotic depression, assessed by treating psychiatrist 4. Dementia, assessed with a dementia screening tool, i.e. the Montreal Cognitive Assessment (MOCA), assessed at the baseline interview. Scoring below 20 points is an indication of the presence of dementia, this score below 20 points will be used as an exclusion criterium 5. Active suicidal thoughts and intent to act on it, assessed at the baseline interview and before the start of the trial. This assessment is based on the Columbia suicide severity rating scale, i.e. question 5 is answered positive “Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?” 6. Metallic devices implanted above the neck, assessed at the baseline interview 7. Patients diagnosed with epilepsy, by a neurologist, assessed at the baseline interview 8. Patients with bipolar II disorder who use anti-depressant medication without anti-manic medication or patients with bipolar I disorder, not using anti-manic medication 9. Substance abuse 4 weeks prior to the study, including high dosage of benzodiazepine, a dosage equivalent higher than 3.0 mg lorazepam, assessed at the baseline interview 10. Pregnancy, if there is any doubt a pregnancy test is performed at baseline 11. Previous treatment with rTMS 12. Inability to understand or comply with study requirements as judged by the investigators, assessed at the baseline interview
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Current primary outcome(s) as of 21/07/2026: Depression severity after 5 weeks of active/sham rTMS measured using Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) at baseline, direct post-treatment, 4 weeks, and 12 weeks follow-up _____ Previous primary outcome(s): Depressive symptoms measured by the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) at baseline and 5 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Current key secondary outcome(s) as of 21/07/2026: 1. Economic evaluation based on the general principles of a cost-effectiveness (utility) analysis, which will be performed alongside the intervention by comparing patients treated with active rTMS with those receiving sham rTMS. Patient-reported outcome measures (i.e., quality-adjusted life years) will be determined. Additionally, societal costs and health consumption will be assessed for the economic evaluation at baseline and 12 weeks post-treatment 2. Response rate defined as 50% reduction of depressive symptoms, based on the HDRS-17, directly after 25 active or sham rTMS sessions 3. Remission rates directly after 25 active or sham rTMS sessions; remission is defined as a HDRS-17 score of 7 and lower 4. Sustained response rate, i.e., those participants, who at 4 weeks and 12 weeks post-treatment, maintain a 50% reduction of depressive symptoms 5. Sustained response rate after 21 weeks post-treatment, in those who received active rTMS, in those who only received sham rTMS, and in those who initially received sham rTMS and later opted to receive active rTMS 6. Prevalence of side effects, including a conversion to mania using the Young Mania rating scale and the rTMS side effects questionnaire, at baseline and during 5 weeks of active or sham rTMS _____ Previous key secondary outcome(s): 1. Economic evaluation based on the general principles of a cost-effectiveness (utility) analysis, which will be performed alongside the intervention by comparing patients treated with active rTMS with those receiving sham rTMS. Patient-reported outcome measures (i.e., quality-adjusted life years) will be determined. Additionally, societal costs and health consumption will be assessed for the economic evaluation at baseline and 12 weeks post-treatment 2. Response rate defined as 50% reduction of depressive symptoms, based on the SIGH ADS, directly after 25 active or sham rTMS sessions 3. Remission rates directly after 25 active | — |
Countries
Netherlands
Outcome results
None listed