Is transcranial magnetic stimulation appropriate for an adult with treatment‑resistant major depressive disorder who has failed an adequate antidepressant trial, and what are the eligibility criteria, standard protocol, contraindications, side effects, and alternative treatment options?

Transcranial Magnetic Stimulation for Treatment-Resistant Depression

Direct Recommendation

TMS is appropriate and should be offered to adults with treatment-resistant major depressive disorder who have failed at least two adequate antidepressant trials of different mechanisms of action, with each trial lasting a minimum of 4 weeks at therapeutic dosing. 1

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Eligibility Criteria

Minimum Requirements for TMS

• Two failed adequate antidepressant trials constitute the standard for treatment-resistant depression qualifying for TMS 1, 2
• Each trial must be at therapeutic dose for at least 4 weeks minimum 3, 1
• The two failures should involve medications with different mechanisms of action 2, 1
• Treatment failures must have occurred within the current depressive episode (or within the last 2 years for prolonged episodes) 1

What Counts as Treatment Failure

• Less than 25% improvement in depressive symptoms after adequate dose and duration defines treatment failure 3, 2
• Discontinuation before 4 weeks due to side effects does NOT count as a failed trial for establishing TRD 3, 1
• Document using Montgomery-Åsberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAM-D) 3

Patients Who Should NOT Be Excluded

• Patients with multiple prior medication failures remain eligible, even if they have failed numerous augmentation strategies 2, 1
• Prior ECT or TMS failure does NOT disqualify patients from subsequent TMS treatment 2, 1
• Comorbid personality disorders or other mental health conditions do not exclude patients unless these conditions clearly preceded and are independent of the MDD diagnosis 2, 1
• Active mild-to-moderate substance use disorder does not exclude patients unless it preceded the MDD diagnosis 2

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Standard Protocol

Treatment Parameters

• Daily left prefrontal TMS for 4-6 weeks (20-30 sessions) is the FDA-approved standard protocol 4
• TMS can be administered adjunctive to current medications 5
• Flexibly dosed up to 30 sessions in acute treatment phase 5

Alternative Protocols

• Theta burst stimulation (intermittent or bilateral sequential) has demonstrated non-inferiority to standard rTMS with shorter treatment times 6
• Low-intensity TMS (30 mT for 60 minutes, 20 sessions) has shown safety and antidepressant effects 7

Maintenance Treatment

• Following acute response, maintenance TMS can sustain benefits over 6 months 5
• 62% of responders maintained their response status during maintenance treatment 5

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Contraindications

Absolute Contraindications

• Metallic implants in the head or neck (excluding dental work)
• Cardiac pacemakers or implanted medical devices in close proximity to the magnetic field
• History of seizure disorder (relative contraindication requiring careful assessment)

Clinical Exclusions

• Severe active substance use disorder not in remission should be excluded 2
• Bipolar depression should be excluded as it is part of bipolar disorder requiring different treatment approaches 2, 3

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Side Effects and Safety Profile

Common Side Effects

• Transient headaches and scalp discomfort are the most common adverse events, typically mild to moderate 8
• Temporary memory precision disruption can occur during active treatment but resolves after treatment 6
• Adverse events demonstrate a predictable time course of resolution 8

Safety Data

• No deaths or seizures reported in comprehensive clinical development program of over 10,000 treatment sessions 8
• Low discontinuation rate of 3-4.5% due to adverse events during acute treatment 5, 8
• Auditory threshold and cognitive function do not change with treatment 8
• TMS is well-tolerated and can be safely administered in an outpatient setting 8

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Expected Outcomes

Efficacy in Clinical Practice

• Response rate of 41-51% and remission rate of 24-35% at 6 weeks in treatment-resistant populations 5
• Mean reduction of 7.8 points on HDRS and 11.4 points on BDI 5
• These outcomes are achieved in highly treatment-resistant populations with mean of 3.4 failed adequate trials 5

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Alternative Treatment Options

If TMS Fails or Is Unavailable

• Electroconvulsive therapy (ECT) remains the gold standard for severe treatment-resistant depression
• Esketamine (intranasal) is FDA-approved for treatment-resistant depression with rapid-acting properties 2
• Augmentation strategies with lithium, thyroid hormone, or atypical antipsychotics
• Switching to antidepressants with different mechanisms of action 3
• Deep brain stimulation (DBS) or vagus nerve stimulation (VNS) for extremely refractory cases, though these are invasive and reserved for patients who have exhausted other options 2

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Critical Clinical Pitfalls to Avoid

• Do not deny TMS based solely on high number of prior treatment failures—these patients remain eligible 1, 2
• Do not count medication trials discontinued before 4 weeks due to side effects as failed trials 3, 1
• Do not exclude patients who previously failed ECT or TMS—they remain candidates for repeat or alternative protocols 2, 1
• Do not require psychotherapy failure as a criterion for TMS eligibility—failed psychotherapy does not count toward TRD definition 2
• Do not relax remission criteria in clinical practice—maintain standard definitions of response (≥50% improvement) and remission 2