Repetitive Transcranial Magnetic Stimulation (rTMS)

Definition and Mechanism of Action

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive brain neuromodulation technique used in the treatment of treatment-resistant major depression. It involves the application of repetitive electromagnetic pulses through a coil placed on the scalp, targeting specific cortical areas involved in mood regulation.

The magnetic field generated induces low-intensity electrical currents in the underlying brain tissue, which modulate neuronal excitability. In depression, the main target is the left dorsolateral prefrontal cortex, which is often underactive in affected individuals. High-frequency pulses applied to this area produce a functional upregulation effect, helping to restore balance in fronto-limbic circuits.

The therapeutic effect appears to be related to:

• Increased functional connectivity between cortical and subcortical regions;
• Modulation of monoaminergic neurotransmitters (especially dopamine and serotonin);
• Stimulation of synaptic neuroplasticity mediated by brain-derived neurotrophic factor (BDNF);
• Anti-inflammatory effects and normalization of dysfunctional cortical activity.

Unlike ECT, rTMS does not induce seizures and does not require anesthesia, making it more tolerable and suitable for repeated outpatient treatment.

Indications in Depression

The primary indication for rTMS is treatment-resistant major depression, defined as failure to respond to at least two antidepressants from different classes, administered at adequate doses and durations. It is approved by regulatory agencies (FDA, EMA) as a second-line therapeutic option.

Additional indications include:

• Major depression with contraindications to pharmacotherapy (e.g., pregnancy, severe side effects);
• Chronic depression or partial response to standard treatment;
• Maintenance phase in patients at risk of relapse but not eligible for ECT;
• Comorbid anxiety or cognitive disorders associated with depression.

It is not recommended as a first-line option for mild or moderate depression, where psychotherapy or pharmacological treatment is often sufficient.

Treatment Protocol

A standard rTMS cycle includes:

• Duration: 20–30 sessions over 4–6 weeks, typically 5 sessions per week;
• Stimulation: high-frequency (10–20 Hz) on the left prefrontal cortex or low-frequency (1 Hz) on the right in cases of contralateral hyperactivity;
• Session duration: approximately 20–40 minutes, depending on the protocol (standard, theta burst, deep-TMS);
• Possibility of maintenance cycles: 1–2 sessions/week for several weeks following the initial response.

The procedure is well tolerated, non-invasive, and compatible with daily life. It does not require hospitalization, anesthesia, or interruption of concurrent medications. Therapeutic response may emerge after 10–15 sessions, with maximum effectiveness by the end of the cycle.

Side Effects and Tolerability

rTMS is generally well tolerated, with a favorable safety profile even in vulnerable individuals. The most common side effects are mild and transient, including:

• Headache or local discomfort on the scalp at the stimulation site;
• Temporary facial muscle pain beneath the coil;
• Fatigue or mild mood disturbances after sessions, especially in the early days;
• Rare risk of seizure, estimated at <1 in 10,000, primarily in predisposed individuals (epilepsy, recent head trauma, cortical lesions, substance abuse).

Unlike ECT, rTMS does not cause significant cognitive changes, and does not require anesthesia or interruption of daily activities. It is also suitable for elderly patients or those with medical comorbidities.

Contraindications

Absolute contraindications to rTMS include:

• Presence of intracranial metal devices (aneurysm clips, brain stents, cochlear implants, deep brain stimulators);
• History of uncontrolled epilepsy or recent non-drug-related seizures;
• Progressive neurological conditions with risk of clinical instability.

Relative contraindications include:

• First-degree family history of seizure disorders;
• Concomitant use of pro-convulsant medications (e.g., high-dose antidepressants, tramadol, clozapine);
• Unstable psychiatric conditions (acute mania, schizophrenia with prominent positive symptoms).

In all such cases, specialist assessment and detailed medical history are essential prior to initiating treatment.

Effectiveness and Guidelines

rTMS has shown efficacy in treatment-resistant depression, with response rates of 40–50% and remission in 20–30% of cases, even among patients who did not respond to conventional pharmacotherapy.

Favorable outcomes are more likely in patients who:

• Have non-psychotic unipolar depression;
• Have low response but good tolerability to medications;
• Are in generally good cognitive and physical health;
• Are undergoing first or second-line advanced treatment (prior to ECT).

International guidelines (APA, CANMAT, NICE) recommend rTMS as a therapeutic option for patients who have not responded to at least one antidepressant, with high-level evidence. It is considered a valid alternative to ECT in patients who refuse or cannot tolerate electroconvulsive therapy.

Final Considerations

rTMS is one of the most promising somatic treatments for treatment-resistant major depression. Its profile of efficacy, tolerability, and non-invasiveness makes it especially suitable for patients who do not respond to or cannot tolerate pharmacological treatments. Its outpatient delivery, integration with other approaches (medications, psychotherapy), and lack of cognitive side effects place it among the most innovative and accessible therapeutic strategies for the future of clinical psychiatry.

References
1. Berlim MT et al. Repetitive transcranial magnetic stimulation for the treatment of major depression: a systematic review and meta-analysis of sham-controlled trials. Psychol Med. 2014;44(2):225–239.
2. O’Reardon JP et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62(11):1208–1216.
3. Lefaucheur JP et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2020;131(2):474–528.
4. George MS et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. Arch Gen Psychiatry. 2010;67(5):507–516.
5. Gaynes BN et al. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic evidence review. J Clin Psychiatry. 2014;75(5):477–489.
6. APA Task Force. Practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry. 2010.
7. Downar J et al. Recommendations for rTMS in clinical practice from the Canadian Network for Mood and Anxiety Treatments (CANMAT). J Affect Disord. 2016;200:19–31.