For a patient with major depressive disorder who has failed at least two adequate antidepressant trials, when is electroconvulsive therapy indicated, what is the recommended treatment schedule, what are the contraindications and common adverse effects, and what alternative or adjunctive treatments should be considered?

ECT in Treatment-Resistant Major Depressive Disorder

ECT should be initiated after failure of at least two adequate antidepressant trials (minimum licensed dose for ≥4 weeks each, with different mechanisms of action), achieving response rates of 50-80% even in severely treatment-resistant patients. 1, 2, 3

Indications for ECT

Standard Criteria for Treatment Resistance

• Minimum requirement: Failure of two adequate antidepressant trials, defined as minimum licensed dose for at least 4 weeks each, with different mechanisms of action according to Neuroscience-based Nomenclature. 1
• Treatment resistance definition: Less than 25% improvement in depression severity (measured by MADRS or similar scales) after adequate trials. 1
• Both failed trials should occur within the current depressive episode and within the past 2 years. 1
• Document treatment adherence through pharmacy records, pill counts, or serum drug levels before declaring treatment failure. 1

Accelerated Indications (Earlier Than Two Trials)

ECT may be considered sooner when: 1

• Life-threatening symptoms present: refusal to eat/drink, severe suicidality, or florid psychosis
• Patient cannot tolerate psychopharmacological treatment at therapeutic doses
• Patient is too incapacitated to take oral medications
• Waiting for medication response would endanger the patient's life

Additional Psychiatric Indications

• Catatonia (first-line treatment). 1, 2
• Neuroleptic malignant syndrome (first-line treatment). 1, 2
• Schizoaffective disorder or schizophrenia with prominent affective symptoms when medication-resistant. 1

Treatment Schedule and Protocol

Acute Phase

• Standard frequency: Three times weekly (typically Monday-Wednesday-Friday). 4
• Minimum course: At least 6 sessions before assessing response. 3
• Expected timeline: 3-5 weeks for acute treatment course. 4
• Response assessment: Measure using MADRS or Hamilton Depression Rating Scale at baseline and after every 2-3 treatments. 1, 3

Response Rates

• Overall effectiveness: 65-80% response rate (≥50% symptom reduction) in treatment-resistant patients. 2, 3, 5
• Remission rates: 50-60% achieve full remission even after multiple medication failures. 3, 5
• Medication resistance impact: Response rate drops to approximately 50% in patients who failed multiple adequate medication trials, compared to 80-90% in non-medication-resistant patients. 6

Contraindications

No Absolute Contraindications Exist

• Cerebral tumor, active chest infection, or recent myocardial infarction are no longer considered absolute contraindications. 1
• Structural CNS abnormalities do not preclude ECT but may affect outcomes. 1

Relative Contraindications Requiring Stabilization

• Active substance withdrawal: Must be medically stabilized (e.g., benzodiazepine protocols for alcohol withdrawal) before initiating ECT. 2
• Increased intracranial pressure: Requires neurosurgical consultation and management before proceeding.
• Recent stroke: Typically wait 4-6 weeks, though not an absolute contraindication.

Important Exclusions for Clinical Trials (Not Clinical Practice)

• Prior failure of deep brain stimulation or vagus nerve stimulation. 1
• Bipolar disorder should be excluded from unipolar depression ECT studies. 1
• Active severe substance use disorder (though single-substance abuse does not preclude ECT). 2

Common Adverse Effects

Cognitive Effects (Most Concerning)

• Memory impairment: Anterograde and retrograde amnesia, typically improving within weeks to months post-treatment. 4
• Cognitive dysfunction: Temporary confusion and disorientation immediately post-treatment.
• Mitigation strategy: Consider unilateral electrode placement if cognitive effects are problematic, though bilateral ECT may be more effective. 6

Cardiovascular Effects

• Transient hypertension and tachycardia during and immediately after seizure induction.
• Requires blood pressure monitoring during each session. 7

Other Common Effects

• Headache (most common, typically responsive to acetaminophen).
• Muscle aches.
• Nausea.

Critical Post-ECT Management Challenge

High Relapse Risk

• Medication-resistant patients: Substantially higher relapse rates (clustered in first 4 months) compared to non-medication-resistant patients. 8, 6
• Key pitfall: Do NOT simply restart the same medication class that failed before ECT—this predicts high relapse rates. 8, 6

Continuation Strategies

Choose one of these approaches: 8, 6

1. Alternative pharmacologic strategy: Switch to a different medication class with different mechanism of action than previously failed trials
2. Maintenance ECT: Continue ECT at reduced frequency (typically weekly, then biweekly, then monthly)
3. Combination approach: New medication class plus maintenance ECT

Alternative and Adjunctive Treatments to Consider

Before ECT (If Not Yet Tried)

• Ketamine/esketamine: Reserve for patients who failed ≥2 adequate antidepressant trials; provides rapid (24-hour) but short-lived (3-7 day) benefit. 1, 7
• Repetitive transcranial magnetic stimulation (rTMS): Less effective than ECT but better cognitive profile; requires daily visits for 4-6 weeks. 1

Augmentation Strategies (If Partial Response to Medications)

• Atypical antipsychotics (aripiprazole, brexiprazole) for augmentation. 7
• Lithium augmentation (particularly effective for maintenance after ECT response).
• Thyroid hormone augmentation (T3).

Head-to-Head Comparison

• ECT and ketamine show similar short-term response rates in clinical trials, but ECT remains the gold standard for treatment-resistant depression. 4
• ECT achieves higher remission rates (50-60%) compared to ketamine's primarily short-term effects. 5, 4

Clinical Decision Algorithm

1. Confirm diagnosis: Severe, persistent MDD with MADRS ≥18 or equivalent severity. 3
2. Document treatment resistance: Verify two adequate trials (minimum dose ≥4 weeks, different mechanisms) with <25% improvement. 1
3. Assess urgency: Life-threatening symptoms → proceed directly to ECT; otherwise, consider ketamine/esketamine or rTMS first. 1
4. Initiate ECT: Bilateral electrode placement, three times weekly, minimum 6 sessions. 3, 4
5. Monitor response: Assess with standardized scales every 2-3 treatments; continue until remission or plateau (typically 8-12 treatments). 3
6. Plan continuation: Do NOT restart failed medication class; choose alternative medication class OR maintenance ECT. 8, 6