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.

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.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.
• 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.

In both conditions the identical setup is used consisting of Neuronavigation, EEG and TMS. Only in the experimental condition the treatment will be EEG-informed. In the control condition the treatment will be applied indepentently of the EEG signal.