Major Depressive DisorderBOSSFRONT2NCT06345651
Brain Oscillation-synchronized Stimulation of the Frontal Cortex in Major Depressive Disorder
A study testing Transcranial Magnetic Stimulation in people with Major Depressive Disorder, run by University Hospital Tuebingen at 1 site in Germany.
Trial summary
Major depressive disorder (MDD) is a common severe psychiatric disease with enormous socioeconomic costs for the patient and society alike. Current pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Transcranial Magnetic Stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteGermany
- Study dates
- 1 Sep 2023to Aug 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects have to be 18 to 65 years old
- Subjects meet DSM-5 criteria for current major depressive disorder (MDD), confirmed with the Structured Clinical Interview for DSM-5.
- Subjects score 20 points or more on the Montgomery-Åsberg Depression Rating Scale (MADRS).
- Subjects must have had at least one non-response (meaning a failure to achieve remission) in a previous pharmacological antidepressant treatment trial of sufficient (meaning a doses considered to be effective (e.g., superior to placebo in controlled clinical trials) and the duration needs to be sufficient to produce a ro-bust therapeutic effect (e.g., 12 weeks)) dosage and duration as assessed by the ATHF; treatment failure can be for the current or any prior depressive episode; medication resistance for the current episode is not required.
- Subject is in good physical and mental health. Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
- Subject is willing to comply with the study restrictions.
- If antidepressant medication is being taken, it has to be taken for at least 2 weeks before inclusion in the study and the dose or active substance must not have been changed. It is necessary that no change in medication will be made until the end of the study (last visit takes place 4 weeks after the last therapy session). If a change in medication is necessary, further study participation is no longer possible.
Who cannot join
- Subject is under the age of legal consent.
- Subject has a diagnosis of bipolar disorder.
- Subject suffers from current symptoms of psychosis.
- Subject has active suicidal ideation with plan and/or intent.
- A current major depressive episode longer than 5 years.
- Subject has a history of substance abuse or dependence within the past 2 years.
Show all 19Show fewer
- Subject has a diagnosis of antisocial or borderline personality disorder.
- Subject suffers from other major psychiatric or medical comorbidity
- Subject has a history of seizure disorder
- Subject has a history of severe head injury with loss of consciousness.
- Subject had a prior brain surgery
- Subjects with intake of pro-convulsive medication, e.g. imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, MDMA (ecstasy), phencyclidine (PCP, angel's dust), ketamine, gamma-hydroxybutyrate (GHB), alcohol, theophylline, in accord with present consensus guidelines on safety, ethical considerations, and application of TMS in clinical practice and research.
- Daily intake of Benzodiazepines other than Lorazepam >1 mg/d
- Subject has a cardiac pacemaker, implanted medication pump, intracardiac line, or acute, unstable cardiac disease.
- Subject has an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head (excluding the mouth) that cannot be safely removed.
- Subject has participated in another study within 2 weeks prior to the first study visit.
- Subject has contra-indications to MRI scans or does not agree that (1) the scans are obtained for research purposes only and will not be evaluated by a qualified neuroradiologist; if an abnormality is present, this may well not be noticed by the doctors, scientists and other staff involved in the study and handling the MRI da-ta; and that (2) if any of the staff involved in the study do suspect a relevant ab-normality to be present in any of the scans, they will reveal this to the subject so that a further diagnostic workup can be conducted outside of the study.
- Subject is pregnant or trying to get pregnant. If someone is not sure weather she is pregnant or not we will test HCG in the urine.
- Planned or anticipated changes of medication within the study period. If a change in medication is necessary, further study participation is no longer possible.
Trial locations and contacts
1 site in 1 country.
Germany1 site, 1 recruiting
- Recruiting
University Hospital Tuebingen
Tübingen, Baden-Wurttemberg, 72076
Anne Lieb, Dr., +4970712980483, anne.lieb@uni-tuebingen.de
Andreas J. Fallgatter, Prof.
About this study
Official title: Brain Oscillation Synchronized Stimulation of the Frontal Cortex: Randomized Controlled Trial Comparing Frontal Theta-oscillation Synchronized Repetitive TMS With Standard TMS in Major Depressive Disorder
Major depressive disorder (MDD) is a common severe psychiatric disease with enormous socioeconomic costs for the patient and society alike. Current pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Using a novel non-invasive brain stimulation method to specifically target and modulate dysfunctional brain oscillations with high spatial and temporal precision this study will investigate the efficacy of EEG-triggered transcranial magnetic stimulation to alleviate de-pressive symptomatology in patients with MDD in a double-blind randomized controlled pilot clinical trial.
Read the detailed description
Evidence from rTMS in the motor system suggests that synchronization of the individual TMS pulses with the negative (in a reference-free Laplacian transform) peak of endogenous EEG-derived brain oscillations results in LTP-like increase in cortical excitability, with the negative peak corresponding to a high-excitability state. A previous proof-of-principle study (BOSSFRONT, funded in the "AKF Anreizprogramm") showed that this approach can be used in patients suffering from major depressive disorder. Recent data from our lab in healthy volunteers indicates that the negative peak of frontocentral theta oscillations may play a similar role in frontal networks, and was therefore chosen with a dorsomedial prefrontal stimulation target in this study aiming to demonstrate therapeutic efficacy of a brain-oscillation synchronized stimulation protocol. The study is a single-site randomized standard TMS therapy-controlled double-blind parallel-group design clinical trial comparing theta-synchronized rTMS over left DMPFC with standard iTBS over left DLPFC in 30 patients with MDD. The primary outcome measure of the study is the difference in MADRS change (baseline / end of treatment) between the two treatment arms.
- Conditions
- Major Depressive Disorder
- Being tested
- Transcranial Magnetic Stimulation
- Keywords
- Noninvasive Brain Stimulation, Transcranial magnetic stimulation, TMS, Personalized Medicine, Closed-Loop, Brain Oscillation, Depression, TBS
- Medical subject headings
- Depressive Disorder, Major, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcranial Magnetic StimulationDevice
Individually MR-neuronavigated TMS, 600 pulses, 120% RMT
| Study group | Role | What they receive |
|---|---|---|
| Theta negative peak triggered TMS of left dmPFC | Experimental | Repetitive TMS (100 Hz triple pulses) of the dmPFC will be applied daily for four weeks (5 sessions per week on working days, 20 sessions in total). Stimulation triggers will be brain oscillation-synchronized based on EEG extracted over left dmPFC, synchronized with the negative peak of endogenous theta oscillations in left dmPFC. Receives: Device: Transcranial Magnetic Stimulation |
| iTBS TMS of left dlPFC | Active comparator | Standard intermittent Theta Burst Stimulation of the dlPFC will be applied daily for four weeks (5 sessions per week on working days, 20 sessions in total). Stimulation triggers will be applied independently of the EEG signal. Receives: Device: Transcranial Magnetic Stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Montgomery-Åsberg Depression Rating Scale (MADRS)
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a questionnaire for external assessment of the severity of a depressive syndrome. The questionnaire consists of 10 questions. The questions are rated on a 7-point scale from 0 to 6. The total score ranges from 0 (best outcome) to 60 (worst outcome) points by summing up. The questionnaire is considered gold standard in the assessment of depressive symptoms. It will be performed at baseline and at the end of the treatment.
Measured: baseline, immediately after the intervention
Secondary outcomes (6)
MADRS (Montgomery-Åsberg Depression Rating Scale) 4 weeks after intervention
Difference in MADRS change 4 weeks after the last treatment session vs. baseline measurement on the day of the first treatment session between the two treatment arms.
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a questionnaire for external assessment of the severity of a depressive syndrome. The questionnaire consists of 10 questions. The questions are rated on a 7-point scale from 0 to 6. The total score can be between 0 (best outcome) and 60 (worst outcome) after summing up. The questionnaire is considered gold standard in the assessment of depressive symptoms. It will be performed at baseline and at the end of the treatment.
Measured: 4 weeks after the last interventional session
HDRS-17 (Hamilton Depression Rating Scale-17)
The HDRS-17 (Hamilton Depression Rating Scale-17) is designed to rate the severity of depression in patients. The rating is performed by a clinician. A score of 0-7 is considered to be normal while a score of 20 or higher indicates at least moderate severity.
Measured: baseline, immediately after the intervention
BDI-2 (Beck Depression Inventory-2)
BDI-2 (Beck Depression Inventory-2) is a 21-question multiple-choice self-report inventory and represents the most widely used psychometric test for assessing the severity of depression in patients. 29-63 points reflect a severe depression.
Measured: baseline, immediately after the intervention
IDS-30 (Inventory of depressive symptoms-30)
The IDS-30 (Inventory of depressive symptomes-30) is considered equivalent to or superior to the standard Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI) tests. The scores ranges from 0 to 84 points.
Patients with scores from 39 are considered severely depressed.
Measured: baseline, immediately after the intervention
Response Rate
Response rate (50% reduction from MADRS) after the last treatment vs. measurement on the day of the first treatment session
Measured: immediately after the intervention
Remission Rate
Remission rate (MADRS under 9 points) after the last treatment
Measured: immediately after the intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Apr 2024
- Study start1 Sep 2023
- Primary completionAug 2025 (estimated)
- Study completionAug 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by University Hospital TuebingenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The study is a single-site randomized standard TMS therapy-controlled double-blind paral-lel-group design clinical trial.
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital Tuebingen
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ulf Ziemann, Prof., Study director, University Hospital TuebingenAndreas J Fallgatter, Prof., Study director, University Hospital Tuebingen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06345651
- Sponsor's protocol ID
- 2023-03, Version 7
- Acronym
- BOSSFRONT2
- Status last verified
- Jan 2024
- First submitted
- 8 Jan 2024
- Last updated
- 3 Apr 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Lieb A, Zrenner B, Becker-Sadzio J, Gordon PC, Kozak G, Zrenner C, Martus P, Ziemann U, Fallgatter A. Brain oscillation-synchronized stimulation for major depression: a randomized controlled trial comparing EEG-triggered repetitive TMS with standard iTBS (Acronym: BOSSFRONT2). Eur Arch Psychiatry Clin Neurosci. 2026 Jun;276(4):1381-1398. doi: 10.1007/s00406-025-02176-9. Epub 2026 Jan 21.
PubMed 41563436
Study at a glance
From the registry record, last updated by the sponsor on 3 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Brain Oscillation Synchronized Stimulation of the Frontal Cortex: Randomized Controlled Trial Comparing Frontal Theta-oscillation Synchronized Repetitive TMS With Standard TMS in Major Depressive Disorder
- ClinicalTrials.gov ID
- NCT06345651
- Acronym / sponsor ID
- BOSSFRONT2 / 2023-03, Version 7
- Conditions
- Major Depressive Disorder
- Keywords
- Noninvasive Brain Stimulation, Transcranial magnetic stimulation, TMS, Personalized Medicine, Closed-Loop, Brain Oscillation, Depression, TBS
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- University Hospital TuebingenUniversity, hospital or other
- Study start
- 1 Sep 2023 (actual)
- Primary completion
- Aug 2025 (estimated)
- Study completion
- Aug 2025 (estimated)
- First posted
- 3 Apr 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Major depressive disorder (MDD) is a common severe psychiatric disease with enormous socioeconomic costs for the patient and society alike. Current pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Using a novel non-invasive brain stimulation method to specifically target and modulate dysfunctional brain oscillations with high spatial and temporal precision this study will investigate the efficacy of EEG-triggered transcranial magnetic stimulation to alleviate de-pressive symptomatology in patients with MDD in a double-blind randomized controlled pilot clinical trial.
Detailed description
Evidence from rTMS in the motor system suggests that synchronization of the individual TMS pulses with the negative (in a reference-free Laplacian transform) peak of endogenous EEG-derived brain oscillations results in LTP-like increase in cortical excitability, with the negative peak corresponding to a high-excitability state. A previous proof-of-principle study (BOSSFRONT, funded in the "AKF Anreizprogramm") showed that this approach can be used in patients suffering from major depressive disorder. Recent data from our lab in healthy volunteers indicates that the negative peak of frontocentral theta oscillations may play a similar role in frontal networks, and was therefore chosen with a dorsomedial prefrontal stimulation target in this study aiming to demonstrate therapeutic efficacy of a brain-oscillation synchronized stimulation protocol. The study is a single-site randomized standard TMS therapy-controlled double-blind parallel-group design clinical trial comparing theta-synchronized rTMS over left DMPFC with standard iTBS over left DLPFC in 30 patients with MDD. The primary outcome measure of the study is the difference in MADRS change (baseline / end of treatment) between the two treatment arms.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- The study is a single-site randomized standard TMS therapy-controlled double-blind paral-lel-group design clinical trial.
| Arm | Type | Receives |
|---|---|---|
| Theta negative peak triggered TMS of left dmPFC | Experimental | Device: Transcranial Magnetic StimulationRepetitive TMS (100 Hz triple pulses) of the dmPFC will be applied daily for four weeks (5 sessions per week on working days, 20 sessions in total). Stimulation triggers will be brain oscillation-synchronized based on EEG extracted over left dmPFC, synchronized with the negative peak of endogenous theta oscillations in left dmPFC. |
| iTBS TMS of left dlPFC | Active comparator | Device: Transcranial Magnetic StimulationStandard intermittent Theta Burst Stimulation of the dlPFC will be applied daily for four weeks (5 sessions per week on working days, 20 sessions in total). Stimulation triggers will be applied independently of the EEG signal. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Subjects have to be 18 to 65 years old
- Subjects meet DSM-5 criteria for current major depressive disorder (MDD), confirmed with the Structured Clinical Interview for DSM-5.
- Subjects score 20 points or more on the Montgomery-Åsberg Depression Rating Scale (MADRS).
- Subjects must have had at least one non-response (meaning a failure to achieve remission) in a previous pharmacological antidepressant treatment trial of sufficient (meaning a doses considered to be effective (e.g., superior to placebo in controlled clinical trials) and the duration needs to be sufficient to produce a ro-bust therapeutic effect (e.g., 12 weeks)) dosage and duration as assessed by the ATHF; treatment failure can be for the current or any prior depressive episode; medication resistance for the current episode is not required.
- Subject is in good physical and mental health. Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
Key exclusion criteria (19 listed)
- Subject is under the age of legal consent.
- Subject has a diagnosis of bipolar disorder.
- Subject suffers from current symptoms of psychosis.
- Subject has active suicidal ideation with plan and/or intent.
- A current major depressive episode longer than 5 years.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcranial Magnetic StimulationIndividually MR-neuronavigated TMS, 600 pulses, 120% RMT | Device | Theta negative peak triggered TMS of left dmPFC, iTBS TMS of left dlPFC |
Primary outcome
Montgomery-Åsberg Depression Rating Scale (MADRS)
Time frame: baseline, immediately after the intervention
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a questionnaire for external assessment of the severity of a depressive syndrome. The questionnaire consists of 10 questions. The questions are rated on a 7-point scale from 0 to 6. The total score ranges from 0 (best outcome) to 60 (worst outcome) points by summing up. The questionnaire is considered gold standard in the assessment of depressive symptoms. It will be performed at baseline and at the end of the treatment.
6 secondary outcomes
MADRS (Montgomery-Åsberg Depression Rating Scale) 4 weeks after intervention
Time frame: 4 weeks after the last interventional session
HDRS-17 (Hamilton Depression Rating Scale-17)
Time frame: baseline, immediately after the intervention
BDI-2 (Beck Depression Inventory-2)
Time frame: baseline, immediately after the intervention
IDS-30 (Inventory of depressive symptoms-30)
Time frame: baseline, immediately after the intervention
Response Rate
Time frame: immediately after the intervention
Remission Rate
Time frame: immediately after the intervention
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2024.
- Derived from this study: PubMed 41563436Lieb A, Zrenner B, Becker-Sadzio J, Gordon PC, Kozak G, Zrenner C, Martus P, Ziemann U, Fallgatter A. Brain oscillation-synchronized stimulation for major depression: a randomized controlled trial comparing EEG-triggered repetitive TMS with standard iTBS (Acronym: BOSSFRONT2). Eur Arch Psychiatry Clin Neurosci. 2026 Jun;276(4):1381-1398. doi: 10.1007/s00406-025-02176-9. Epub 2026 Jan 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ulf Ziemann, Prof. study director
University Hospital Tuebingen
Andreas J Fallgatter, Prof. study director
University Hospital Tuebingen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Transcranial Magnetic Stimulation in people with Major Depressive Disorder, run by University Hospital Tuebingen at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Anne Lieb, Dr. (+4970712980483, anne.lieb@uni-tuebingen.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Montgomery-Åsberg Depression Rating Scale (MADRS) (time frame: baseline, immediately after the intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06345651, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2024.