What is the recommended protocol for intravenous (IV) ketamine administration to treat depression?

Evidence-Based Protocol for IV Ketamine in Depression

For treatment-resistant depression, administer IV ketamine at 0.5 mg/kg infused over 40 minutes, which is the standard evidence-based protocol supported by multiple studies and represents the most commonly validated approach for achieving rapid antidepressant effects. 1, 2

Patient Selection Criteria

• Treatment resistance: Patients must have failed at least 2 adequate antidepressant trials before initiating ketamine 2
• Particularly valuable for: Patients with acute suicidal ideation given rapid onset of action (effects begin within 40 minutes) 1, 2
• Can be used in: Both major depressive disorder and bipolar depression (when added to mood stabilizers like lithium or valproate to mitigate manic switch risk) 2

Standard Dosing Protocol

Initial/Induction Dose

• Standard dose: 0.5 mg/kg IV infused over 40 minutes 1, 2
• Alternative slower infusion: 0.5 mg/kg over 100 minutes may provide similar efficacy with potentially better tolerability 1, 3
• Lower doses: 0.2 mg/kg has shown efficacy in emergency department settings for suicidal ideation, though this is less studied for general depression treatment 1, 4

Important Dosing Considerations

• Higher doses (>0.5 mg/kg) do not provide greater treatment response and increase side effects 4
• Doses as low as 0.2 mg/kg may be efficacious, with increasing dose response at 0.5 mg/kg 4
• The FDA-approved anesthetic dosing (1-4.5 mg/kg) is NOT appropriate for depression treatment 5

Serial Infusion Protocol

Acute Phase Treatment

• Frequency: Twice weekly infusions until remission is achieved or 4-6 total infusions are completed 1, 3
• Alternative schedule: Three times per week for 2 weeks (6 total infusions) has been studied 1
• Response assessment: Evaluate for 50% reduction in depressive symptoms at 24 hours post-infusion 1

Maintenance Phase

• Initial maintenance: Continue infusions every 2-4 days if initial response achieved 6
• Long-term maintenance: Frequency decreases from every 5 days to every 3-4 weeks over the first 5 months 7
• Duration: Mean of 18 total infusions over 12 months in real-world VA data 7
• Sustained benefit: Symptom improvements achieved within first 6 weeks can be maintained for at least 6 months with decreasing infusion frequency 7

Administration Requirements

Pre-Treatment Preparation

• Dilution required: Do NOT administer 100 mg/mL concentration IV without dilution 5
• Proper dilution: Mix with equal volume of Sterile Water, Normal Saline, or 5% Dextrose 5
• Use immediately after dilution 5
• Consider antisialagogue: May administer prior to infusion due to potential for salivation 5

Monitoring During Infusion

• Continuous vital sign monitoring required: Heart rate, blood pressure, oxygen saturation 5
• Emergency airway equipment must be immediately available 5
• Administered by or under direction of physicians experienced in anesthesia administration 5

Post-Treatment Monitoring

• 2-hour post-treatment observation period required (particularly important for esketamine formulations under REMS) 2
• Monitor for dissociative symptoms: Usually mild and transient, occurring around time of treatment 6, 8
• Blood pressure elevation: Transient increases common but usually well-tolerated 6

Expected Clinical Outcomes

Timeline of Response

• Onset: Antidepressant effects begin within hours, peak at approximately 24 hours 6, 8
• Duration of single dose: Effects last 3-12 days after single infusion 6, 8
• 6-week outcomes: 26% achieve 50% improvement (response), 15% achieve remission (PHQ-9 ≤5) 7
• Sustained response: Improvements at 6 weeks are similar at 12 and 26 weeks with maintenance infusions 7

Antisuicidal Effects

• Rapid reduction in suicidal ideation: Effects begin at 40 minutes with largest effect sizes (d=1.05 at 40 min, d=2.36 in high-baseline SI patients) 1
• Duration: Antisuicidal effects can persist for up to 10 days following single infusion 1
• Independent effect: May be partially independent of general antidepressant effects 1, 2

Common Pitfalls and Safety Considerations

Side Effects Profile

• Dissociative/psychotomimetic symptoms: Almost always mild and transient, rarely cause discontinuation 6
• Cardiovascular: Transient elevation of heart rate and blood pressure common 6
• Respiratory depression: Rare but possible; have bag-valve-mask ventilation available 9
• Genitourinary pain: Case reports with chronic use; consider cessation if persistent genitourinary symptoms develop 5

Contraindications

• Avoid in: Uncontrolled cardiovascular disease, cerebrovascular disease, uncontrolled hypertension, active psychosis, severe hepatic dysfunction, elevated intracranial/intraocular pressure 9, 5
• Pregnancy: Not recommended 9

Augmentation Strategy

• Consider benzodiazepine co-administration: May reduce emergence reactions and dissociative symptoms, though evidence is mixed 5
• Continue concurrent antidepressants: Ketamine is typically used as add-on therapy to existing treatment 1, 2

Key Limitations

• Real-world response rates are modest: Only 26% response and 15% remission at 6 weeks in VA data 7
• Long-term safety data limited: Relatively little known about effects beyond 12 months 8
• Abuse potential: Concerns exist with repeated dosing, though data are limited 8
• Optimal maintenance strategy unclear: Frequency and duration of maintenance infusions not well-established 2, 7
• Quality of evidence: Overall low quality with small sample sizes in many studies 4