What is the role of ketamine in treating adults with treatment-resistant depression, particularly those with a history of suicidal ideation or severe depressive symptoms?

Ketamine in Treatment-Resistant Depression

Ketamine should be reserved exclusively for adults with treatment-resistant depression who have failed at least 2 adequate antidepressant trials at appropriate doses and durations, and should never be used as first-line therapy. 1

Patient Selection Criteria

Reserve ketamine for treatment-resistant cases only:

• Patients must have documented failure of ≥2 adequate antidepressant trials (appropriate dose and duration) 1, 2
• The 2022 VA/DoD Clinical Practice Guidelines represent a major shift from 2016, now suggesting ketamine or esketamine as treatment options specifically for this population 1
• Continue or initiate second-generation antidepressants alongside ketamine therapy 1

Rapid Antidepressant Effects

Ketamine produces uniquely rapid symptom improvement:

• Significant improvement in depressive symptoms occurs within 24 hours after single-dose administration 1
• Effects persist for 3-7 days when added to ongoing antidepressant treatment 1
• In real-world Canadian clinic data, response rate (≥50% symptom reduction) was 27% and remission rate was 13% after four infusions 3

Suicidal Ideation: Promising but Limited Evidence

Ketamine shows rapid reduction in suicidal ideation, but critical limitations exist:

• The FDA explicitly states that effectiveness in preventing suicide or reducing suicidal ideation/behavior has not been established 1
• Meta-analysis data shows significant reduction in suicidal ideation at 4 hours post-infusion (standardized mean difference = -0.51), persisting until 72 hours but not thereafter 4
• Effect sizes are largest at 40 minutes (d = 1.05 overall; d = 2.36 in patients with high baseline suicidal ideation) 5, 2
• Standard antidepressant treatments do not provide robust and rapid relief of suicidal ideation, and even ECT may not reduce suicidal ideation for 1-2 weeks, highlighting the unmet need 5, 1

Critical caveat: There are virtually no data on effects on actual suicidal behavior (attempts or completed suicide), only on suicidal thoughts 4

Dosing Protocols

Standard IV ketamine dosing:

• 0.5 mg/kg IV infused over 40 minutes is the evidence-based standard dose 5, 2
• Serial infusion protocol: twice weekly until remission or 4-6 total infusions completed 2
• Response criteria: ≥50% reduction in depressive symptoms at 24 hours post-infusion 2

Alternative dosing for acute suicidal ideation in emergency settings:

• Lower doses (0.2-0.25 mg/kg) show rapid antisuicidal effects beginning within 40 minutes and lasting up to 10 days 2

Emerging oral ketamine data:

• A 2025 midazolam-controlled RCT showed oral racemic ketamine (3 mg/kg, mean dose 180 mg) significantly reduced suicidal ideation at 4 hours, Day 3, and Day 7 compared to active control 6
• Oral ketamine is the most practical route for mainstream psychiatry, though bioavailability is only 20-25% 7

Safety Profile and Monitoring Requirements

Short-term adverse effects requiring monitoring:

• Dissociative symptoms (dose-dependent; hallucinations in ~20%, nightmares in ~12% at 0.5 mg/kg) 2
• Hypertension requiring blood pressure monitoring during and after infusion 1, 2
• Sedation and potential respiratory depression 1
• Nausea, ataxia, transient dissociation 2, 6
• Dissociation severity significantly reduces with subsequent infusions 3

Long-term concerns requiring ongoing surveillance:

• Most significant limitation: absence of long-term safety and efficacy data 1
• Potential for abuse and misuse 1
• Unknown neurocognitive effects with long-term use 1
• Possible urologic toxicity with chronic administration 1
• Risk of substance use disorder development 1

Additional Benefits Beyond Depression

Ketamine demonstrates effectiveness for comorbid symptoms:

• Anxiolytic effects with significant improvement in GAD-7 scores 3
• Improved overall psychosocial function (Sheehan Disability Scale) 3
• Particularly effective in patients with mixed features (anxiety, irritability, agitation), who experienced significantly greater reduction in overall depressive symptoms and suicidal ideation compared to non-mixed features patients 8

Clinical Implementation Algorithm

1. Verify eligibility: Document ≥2 failed adequate antidepressant trials and confirm moderately severe depression 1, 2
2. Initiate or continue second-generation antidepressant alongside ketamine 1
3. Standard protocol: Administer 0.5 mg/kg IV over 40 minutes, twice weekly 2
4. Monitor: Blood pressure, dissociative effects, respiratory status during and after infusion 1, 2
5. Assess response: Evaluate at 24 hours post-infusion for ≥50% symptom reduction 2
6. Duration: Continue until remission or 4-6 total infusions completed 2
7. Maintenance strategy: Effects are transient (3-7 days), requiring development of means to sustain any benefit 1, 4

Common Pitfalls to Avoid

• Never use ketamine as first-line therapy - this represents inappropriate use 1
• Do not rely on ketamine alone for suicide prevention - the FDA has not established effectiveness for preventing suicide or reducing suicidal behavior 1
• Do not assume long-term safety - data beyond several weeks are lacking 1
• Do not discontinue concurrent antidepressants - ketamine should augment, not replace, standard treatment 1