What is the safest evidence‑based way to add ketamine for a patient with major depressive disorder who remains symptomatic despite sertraline 200 mg, quetiapine 50 mg, lamotrigine 200 mg, and bupropion 75 mg?

Ketamine for Treatment-Resistant MDD: Evidence-Based Protocol

For this patient with treatment-resistant MDD on multiple medications, initiate intravenous ketamine at 0.5 mg/kg infused over 40 minutes, administered twice weekly for 4-6 total infusions, as add-on therapy to the existing medication regimen. 1, 2, 3

Patient Qualification

This patient meets criteria for ketamine therapy based on current guidelines:

• Treatment resistance confirmed: Failed adequate trials of sertraline (200mg), bupropion (75mg), plus augmentation with quetiapine (50mg) and lamotrigine (200mg) 1, 4
• Guideline support: The 2022 VA/DoD guidelines represent a significant shift from 2016, now suggesting ketamine/esketamine for patients who have not responded to several adequate pharmacologic trials 1
• Not first-line: Ketamine is appropriately reserved for patients for whom previous therapies have failed, which applies here 1, 4

Standard Dosing Protocol

Intravenous ketamine 0.5 mg/kg over 40 minutes is the evidence-based standard dose supported by multiple RCTs and meta-analyses: 1, 2, 4, 3

• Frequency: Twice weekly infusions until remission or 4-6 total infusions completed 2, 3
• Response assessment: Evaluate for ≥50% reduction in depressive symptoms at 24 hours post-infusion 2, 3
• Onset of action: Significant improvement typically occurs within 24 hours 1, 4
• Duration of single-dose effect: 3-4 days for depression symptoms 1, 4

Administration Considerations

Continue all current medications during ketamine treatment—the evidence specifically supports ketamine as add-on therapy to ongoing antidepressants: 1

• Meta-analysis of 20 RCTs showed ketamine added to ongoing antidepressant treatment resulted in significant improvements for up to 7 days 1
• The patient's lamotrigine (mood stabilizer) should be maintained, as guidelines support adding ketamine to mood stabilizers to mitigate manic switch risk in patients with any bipolar features 2

Expected Timeline and Outcomes

Acute phase (Weeks 1-3):

• Response rates: 41.7% after 6 infusions in treatment-resistant populations 5
• Remission rates: 14.3-16.7% after serial infusions 5
• Effects begin within 24 hours but may not be sustained beyond one week after single infusion 1, 6

Critical limitation: Most responders relapse within 2 weeks after the final infusion without maintenance strategy 5

Safety Monitoring Requirements

Mandatory monitoring during and after infusion: 4

• Common adverse effects: Transient dissociation, nausea, ataxia, increased blood pressure 4, 3
• Psychotomimetic effects are dose-dependent: At 0.5 mg/kg, expect hallucinations in ~20% and nightmares in ~12% of patients 2, 3
• Blood pressure elevation: Monitor during infusion and for 2 hours post-treatment 4
• Dissociative symptoms: Typically limited to time of treatment and resolve quickly 7

Alternative Considerations

Esketamine intranasal is an FDA-approved alternative but has significant practical barriers: 1, 4

• Requires REMS certification for pharmacy and healthcare setting 1, 4
• Mandatory 2-hour post-treatment monitoring 1, 4
• Twice-weekly dosing as augmentation improves response and remission rates by 16% at 4 weeks 4, 8
• More evidence for longer-term maintenance use compared to IV ketamine 1

Lower doses (0.2-0.25 mg/kg) are supported only for emergency department settings with acute suicidal ideation, not for standard TRD treatment 1, 2, 3

Critical Pitfalls to Avoid

Do not use ketamine as monotherapy—the strongest evidence supports it as augmentation to ongoing antidepressants: 1

Do not expect sustained effects without a maintenance plan—ketamine lacks established long-term efficacy data, and most evidence is for short-term (7-day) efficacy: 1, 4

Do not overlook the relapse risk—all but one responder in dose-escalation studies relapsed within 2 weeks after final infusion, indicating need for transition planning: 5

Verify trained administration personnel—ketamine for TRD is generally safe when administered by trained professionals, but requires proper monitoring infrastructure: 6

Maintenance Strategy Gap

Major evidence limitation: Optimal maintenance strategies after acute response are not well-established: 2

• Consider transition to esketamine for maintenance if acute response achieved, as it has more evidence for longer-term use 1
• Alternative: Continue twice-weekly infusions for responders, though long-term safety data are limited 1, 4
• Plan for potential need to resume or intensify baseline antidepressant regimen 5