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

Ketamine for Treatment-Resistant Depression

Ketamine is a highly effective rapid-acting antidepressant and antisuicidal agent for treatment-resistant depression (TRD), demonstrating significant symptom reduction within hours of administration compared to traditional antidepressants that may take weeks to work. 1

Mechanism of Action and Pharmacology

• Ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist that produces rapid antidepressant effects in both unipolar and bipolar treatment-resistant depression 1
• The standard protocol for intravenous administration is 0.5 mg/kg infused over 40 minutes, though other routes of administration have been studied 1, 2
• Ketamine is a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, with (S)-ketamine (esketamine) now available as an FDA-approved nasal spray for TRD 3

Efficacy in Treatment-Resistant Depression

Antidepressant Effects

• Meta-analyses show substantial antidepressant effects in real-world settings with response rates of approximately 45% and remission rates of 30% 4
• Single ketamine infusions produce significant antidepressant effects within 24 hours compared to placebo (midazolam) 5
• Repeated ketamine infusions demonstrate cumulative antidepressant effects, with 59% of patients meeting response criteria (≥50% decrease in MADRS scores) after a series of infusions 5
• The median number of infusions required to achieve response is three, with effects maintained through weekly maintenance infusions 5

Antisuicidal Effects

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

Administration Protocols

Intravenous Administration

• Standard protocol: 0.5 mg/kg infused over 40 minutes 1
• Single infusions show transient effects, while repeated infusions (typically 2-3 times per week for 2 weeks) demonstrate more sustained benefits 5
• Maintenance infusions (weekly or biweekly) may prolong response in patients who initially respond to ketamine 5

Alternative Routes of Administration

• Oral ketamine (0.25-7 mg/kg or 50-300 mg per dose) shows promise for depression treatment despite lower bioavailability (20-25%) 2
• Intranasal ketamine (esketamine) is FDA-approved for TRD in conjunction with oral antidepressants 3
• Other studied routes include sublingual, transmucosal, intramuscular, subcutaneous, and rectal administration 2

Safety and Tolerability

• Ketamine is generally well-tolerated with low attrition rates (3.1%) in clinical trials 6
• Common acute side effects include drowsiness, dizziness, poor coordination, blurred vision, and dissociative symptoms 6
• Approximately one-third of patients experience protocol-defined hemodynamic changes requiring monitoring 6
• Transient psychotomimetic and dissociative symptoms occur but typically resolve within hours 6
• No cases of persistent psychotomimetic effects, serious adverse medical effects, or increased substance use have been reported in follow-up studies 6

Clinical Applications and Considerations

• Ketamine should be considered for patients with TRD who have failed at least two adequate trials of antidepressants 1, 4
• Particularly valuable for patients with acute suicidal ideation given its rapid onset of action 1
• More severely treatment-resistant cases may have lower remission rates but can still benefit from ketamine treatment 4
• Therapeutic effects do not significantly decline with repeated treatments, supporting the use of maintenance protocols 4

Limitations and Future Directions

• Effects are typically transient after single infusions, requiring repeated administration 5
• Long-term safety and efficacy data beyond several weeks are limited 3
• Concerns regarding abuse potential and long-term side effects require further investigation 3
• Research is needed to identify biomarkers for predicting response and developing next-generation rapid-acting antidepressants with fewer side effects 3

Emergency Department Applications

• Ketamine shows promise for rapid reduction of suicidal ideation in emergency department settings 1
• Lower doses (0.2 mg/kg over 1-2 minutes) have shown significant reductions in SI for up to 10 days following infusion 1
• May provide a bridge treatment for acutely suicidal patients until traditional treatments take effect 1