Trans cranial magnetic stimulation in bipolar depression

INTERVENTION: 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 assigned to one of the two treatment groups and will receive active or sham rTMS for 25 rTMS sessions (i.e. 5 weeks). Phase 2 comprises of two follow‐up measurements, one at 4 weeks and one at 12 weeks after treatment with active or sham rTMS. After the 12 weeks of follow‐up patients allocated to sham rTMS will be offered active rTMS. In Phase 3 all patients will be followed for 21 weeks to determine the sustained response rate to treatment. Patients will be randomly allocated to the active rTMS or sham rTMS group. Stratified across sites, we will use block randomization, using random sequences of block size 4 and 6. This approach ensures treatment assignment balance within each complete block and minimizes the imbalance of group sizes within clinical centers, thus correcting for confounding from possible differences between treatment sites (such as differences in experience with rTMS). Block randomization will be done using Castor. CONDITION: 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 PRIMARY OUTCOME: 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 OUTCOME: ; 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 or sham rTMS sessions; remission is defined as a SIGH ADS score of 8 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 6 weeks of active or sham rTMS.; 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 medicati