Transcranial magnetic stimulation in bipolar depression

ISRCTN	ISRCTN16011816
DOI	https://doi.org/10.1186/ISRCTN16011816
Protocol serial number	NL77251.029.21
Sponsor	Amsterdam UMC Location VUmc
Funder	ZonMw

Submission date: 15/01/2022
Registration date: 31/01/2022
Last edited: 21/07/2026

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Mental and Behavioural Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Bipolar depression causes extreme mood swings that include emotional highs and lows). New treatments are necessary for patients with bipolar depression since more than 35% of these patients are medication-resistant. As a consequence, there is a high burden of illness for patients with bipolar depression, leading to increased suicide rates, inability to maintain proper work and/or social role functions, and reduced quality of life. A possible new treatment strategy is repetitive transcranial magnetic stimulation (rTMS), which is effective in patients with unipolar depression. However, it is unknown whether it is also effective in those with bipolar depression. The aim of this study is to determine whether rTMS is effective in patients with bipolar depression who did not respond to two or more adequately dosed medication trials.

Who can participate?
Patients aged 18 years and over with bipolar depression who did not respond to two or more adequately dosed medication trials, in the current depressive episode.

What does the study involve?
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

What are the possible benefits and risks of participating?
rTMS is a safe treatment with few side effects. Participants could benefit from rTMS treatment but the current study is necessary to determine if it is an effective treatment in patients with bipolar depression.

Where is the study run from?
Amsterdam UMC Location VUmc (Netherlands)

When is the study starting and how long is it expected to run for?
January 2022 to February 2027

Who is funding the study?
ZonMw (Netherlands)

Who is the main contact?
E van Exel
tbide@amsterdamumc.nl

Contact information

Prof Eric van Exel
Scientific, Principal investigator

GGZinGeest/Amsterdam UMC
Amstelveenseweg 589
Amsterdam
1097AN
Netherlands

ORCID ID	0000-0002-5737-9600
Phone	+31 (0)207885000
Email	tbide@ggzingeest.nl

Mrs Eva Oostra
Scientific

Oldenaller 1
Amsterdam
1081JC
Netherlands

ORCID ID	0009-0008-2534-8800
Phone	+31 629680818
Email	e.oostra@amsterdamumc.nl

Study information

Primary study design	Interventional
Study design	Pragmatic multicentre randomized clinical trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Efficacy of repetitive Transcranial magnetic stimulation in patients with medication-resistant BIpolar DEpression: a multicenter, randomized, double-blind, sham-controlled study
Study acronym	TBIDE
Study objectives	To determine if active repetitive transcranial magnetic stimulation (rTMS), compared to sham rTMS, will result in a larger reduction of depressive symptoms, in patients with treatment-resistant bipolar depression
Ethics approval(s)	Approved 12/01/2022, METC Amsterdam UMC (Locatie VUmc Van der Boechorststraat 6B, Amsterdam, 1081 BT, Netherlands; +31 20-4445585; metc@nedmec.nl), ref: NL 77251.029.21
Health condition(s) or problem(s) studied	Treatment-resistant bipolar depression, i.e. patients with bipolar depression who did not respond to two or more adequately dosed medication trials
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.
Intervention type	Device
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	MagStim, MagVenture, Neurosoft, DeyMed, Mag&More
Primary outcome measure(s)	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
Key secondary outcome measure(s)	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 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.
Completion date	01/02/2027

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	110 Years
Sex	All
Target sample size at registration	166
Total final enrolment	108
Key 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
Key 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
Date of first enrolment	01/05/2022
Date of final enrolment	18/06/2026

Locations

Countries of recruitment

Netherlands

Study participating centres

Amsterdam UMC, location VUmc

Amsterdam
1081 HV
Netherlands

GGZinGeest

Amsterdam
1081 JC.
Netherlands

PSQ

Rotterdam and the Hague
2512 VA
Netherlands

Altrecht

Utrecht
3512 PG
Netherlands

Radboud UMC

Nijmegen
6525 GA
Netherlands

ProPersona

Nijmegen
6534 AM
Netherlands

UMC Groningen

Groningen
9713 GZ
Netherlands

GGZ Delfland

Delft
Netherlands

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan	Data are available on request: E.vanexel@ggzingeest.nl

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Other files	Power calculation and inclusion total 2024		21/07/2026	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN16011816 Power_calc_T-BIDE_trialreg.pdf: Power calculation and inclusion total 2024

Editorial Notes

21/07/2026: The following changes were made to the study record:
1. An addition file was uploaded.
2. The Completion date was changed from 01/02/2025 to 01/02/2027.
3. The primary outcome(s) were changed.
4. The key secondary outcome(s) were changed.
5. The total final enrolment was added.
6. The Date of first enrolment was changed from 01/02/2022 to 01/05/2022.
7. The Date of final enrolment was changed from 01/02/2024 to 18/06/2026.
8. The study participating centres were updated.
9. Contact details updated.
20/01/2022: Trial's existence confirmed by ZonMw.