What is the role of ketamine in treating treatment-resistant depression in psychiatry?

Ketamine in Treatment-Resistant Depression

Ketamine represents a promising treatment option for treatment-resistant depression (TRD), showing rapid antidepressant effects, but more data is needed before making definitive clinical recommendations, especially regarding its long-term use. 1, 2

Mechanism and Efficacy

• Ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist that produces rapid antidepressant effects in both unipolar and bipolar treatment-resistant depression 2
• The standard protocol for intravenous administration is 0.5 mg/kg infused over 40 minutes, though other routes have been studied 2
• Ketamine demonstrates rapid reduction in depressive symptoms, with effects beginning as quickly as 40 minutes post-infusion 2
• In a recent randomized controlled trial comparing ketamine to ECT, ketamine was found to be noninferior to ECT for treatment-resistant major depression without psychosis (55.4% response rate for ketamine vs. 41.2% for ECT) 3

Antisuicidal Effects

• Ketamine produces rapid reductions in suicidal ideation (SI) across multiple rating scales, with effects beginning as quickly as 40 minutes post-infusion 2
• Effect sizes for SI reduction are largest at 40 minutes (d=1.05), diminishing to moderate effect sizes at 230 minutes (d=0.45) 2
• In patients with high baseline SI, effect sizes are substantially larger (d=2.36 at 40 minutes and d=1.27 at 230 minutes) 2
• Some evidence suggests ketamine's antisuicidal effects may be independent of its general antidepressant effects, but this remains inconclusive 1

Administration Routes and Protocols

• While intravenous ketamine is the most studied approach (0.5 mg/kg over 40 minutes), other routes have shown promise 2, 4:
  • Oral (bioavailability ~20-25%, doses ranging from 0.25 to 7 mg/kg) 5
  • Intranasal, intramuscular, subcutaneous, sublingual, and transmucosal 4
• For intravenous administration, safety and efficacy have been demonstrated in sessions ranging between 2 and 100 minutes in duration 4
• Repeated ketamine infusions have shown cumulative and sustained antidepressant effects, with 59% of participants meeting response criteria after a series of infusions 6

Safety and Tolerability

• In a large study of 205 ketamine infusions in 97 patients with TRD, ketamine was generally safe and well-tolerated 7
• Only 1.95% of infusions were discontinued due to adverse events, with an overall attrition rate of 3.1% 7
• Common side effects in the first 4 hours after infusion include drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal 7
• Approximately one-third of individuals experience protocol-defined hemodynamic changes 7
• Ketamine results in small but significant increases in psychotomimetic and dissociative symptoms, but no cases of persistent psychotomimetic effects were reported 7

Clinical Applications and Considerations

• Ketamine should be considered for patients with TRD who have failed at least two adequate trials of antidepressants 2
• It is particularly valuable for patients with acute suicidal ideation given its rapid onset of action 2
• For maintenance treatment, the frequency is best individualized with ketamine dosed before the effect of the previous session wears off 4
• Weekly maintenance infusions may help sustain antidepressant effects in responders 6

Important Caveats

• Despite promising results, the evidence supporting ketamine's clinical use for TRD remains preliminary 1
• The risks of ketamine must be weighed against potential benefits 1
• Long-term effects and optimal maintenance strategies require further study 1, 6
• There is limited data on strategies for maintaining ketamine's antidepressant properties, and concerns exist regarding repeated administration 1
• From a practical standpoint, subcutaneous, intranasal, and oral ketamine warrant further study for outpatient use 4
• Risk of abuse must be considered, especially with domiciliary treatment 4