What is the recommended dosing of ketamine hydrochloride (intravenous) for a patient with treatment-resistant depression?

Ketamine Hydrochloride Dosing for Treatment-Resistant Depression

For treatment-resistant depression, administer intravenous ketamine hydrochloride at 0.5 mg/kg infused over 40 minutes, which is the standard evidence-based protocol supported by the American Psychiatric Association and multiple clinical trials. 1

Patient Selection Criteria

Before initiating ketamine therapy, confirm treatment resistance by documenting:

• At least 2 failed adequate antidepressant trials (minimum 4-6 weeks duration at therapeutic doses) 2
• Moderately severe depression as measured by standardized rating scales 2
• For bipolar depression, ensure concurrent mood stabilizer therapy (lithium or valproate) to mitigate manic switch risk 1

Standard Dosing Protocol

Acute Phase Treatment

Primary regimen: 0.5 mg/kg IV infused over 40 minutes 1, 3, 4

• Frequency: Twice weekly until remission or completion of 4-6 total infusions 1
• Response assessment: Evaluate for ≥50% reduction in depressive symptoms at 24 hours post-infusion 1
• Alternative schedule: Three times per week for 2 weeks has been studied 1

Dose Modifications

Lower doses may be appropriate in specific circumstances:

• 0.2-0.25 mg/kg for patients with acute suicidal ideation in emergency settings, administered over 1-2 minutes, which minimizes psychotomimetic effects while preserving antisuicidal benefits 1, 5, 6
• Some patients respond to doses as low as 0.1 mg/kg, while others may require up to 0.75 mg/kg 7

Slower infusion rates:

• 0.5 mg/kg over 100 minutes (instead of 40 minutes) may provide similar efficacy with potentially better tolerability 1, 6

Clinical Response Timeline

Rapid onset of action distinguishes ketamine from traditional antidepressants:

• Antisuicidal effects begin within 40 minutes post-infusion, with largest effect sizes (d=1.05) at this timepoint 1, 5
• Antidepressant effects persist for 2-3 days after single infusion 1
• Significant improvements remain through day 7 when added to ongoing antidepressant treatment 1
• In emergency settings, effects on suicidal ideation can persist up to 10 days following single infusion 1, 5

Safety and Tolerability Profile

Common acute effects (dose-dependent):

• Drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal occur in the first 4 hours post-infusion 3
• Psychotomimetic effects at 0.5 mg/kg: hallucinations (20%), nightmares (12%) 5, 6
• Approximately one-third of patients experience protocol-defined hemodynamic changes 3
• Dissociative symptoms occur but are transient 3, 4

Discontinuation rates are low:

• Only 1.95% of infusions discontinued due to adverse events 3
• Overall attrition rate of 3.1% across clinical trials 3
• No cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in long-term follow-up 3

Maintenance Strategies

For patients who respond to acute treatment:

• Continue ketamine dosing "a little before the effect of the previous session is expected to wear off" 7
• Treatment may be continued for weeks to years in refractory cases to extend and maintain treatment gains 7
• Optimal maintenance frequency should be determined by monitoring for symptom return, typically occurring 2-7 days after single infusion 1, 6

Critical Caveats

Monitoring requirements:

• Esketamine (intranasal formulation) requires REMS certification and mandatory 2-hour post-treatment monitoring 1, 5
• IV ketamine administered in clinical settings requires hemodynamic monitoring during and after infusion 3

Evidence limitations:

• Long-term efficacy and safety data remain limited, with most evidence from small sample sizes 1, 5
• Optimal maintenance strategies are not well-established 1, 5
• Effectiveness in preventing completed suicide has not been established despite FDA approval for acute suicidal ideation 5
• The antisuicidal effects may be partially independent of general antidepressant effects, though this requires further investigation 1, 5

Comparative effectiveness:

• In the largest head-to-head trial (ELEKT-D), ketamine demonstrated noninferiority to ECT for treatment-resistant major depression without psychosis, with 55.4% response rate versus 41.2% for ECT 4
• Ketamine was associated with dissociation, while ECT caused memory impairment and musculoskeletal adverse effects 4