Maximum Dose of Intravenous Ketamine for Treatment-Resistant Depression
The maximum dose of intravenous ketamine for treatment-resistant depression is 0.5 mg/kg infused over 40 minutes, which represents the standard evidence-based protocol supported by the American Psychiatric Association and multiple clinical guidelines. 1
Standard Dosing Protocol
The established maximum therapeutic dose is 0.5 mg/kg administered intravenously over 40 minutes, which has been validated across multiple high-quality studies and represents the ceiling for routine clinical use in depression treatment. 1, 2
This dose produces response rates of 61% when used as add-on therapy to mood stabilizers in treatment-resistant depression. 1
A landmark 2023 trial (ELEKT-D) demonstrated that ketamine at 0.5 mg/kg twice weekly was noninferior to electroconvulsive therapy, with 55.4% response rates in 195 patients with treatment-resistant major depression. 3
Dosing Frequency and Treatment Course
Twice weekly infusions until remission or 4-6 total infusions represents the standard acute phase treatment protocol. 1
Alternative schedules of three times per week for 2 weeks have been studied, though twice weekly remains most common. 1
Response assessment should evaluate for 50% reduction in depressive symptoms at 24 hours post-infusion. 1
Lower Dose Options for Specific Indications
For acute suicidal ideation in emergency settings, 0.2 mg/kg IV over 1-2 minutes has demonstrated efficacy with potentially fewer psychotomimetic effects, though this is below the standard depression treatment dose. 1, 2
This lower emergency dose produces significant reductions in suicidal ideation lasting up to 10 days. 1
Doses of 0.2-0.25 mg/kg minimize dissociative side effects while preserving antisuicidal benefits. 2
Critical Safety Considerations
Do not exceed 0.5 mg/kg for depression treatment, as higher doses substantially increase psychotomimetic side effects without established additional benefit:
At 0.5 mg/kg, hallucinations occur in 20% and nightmares in 12% of patients. 1
Doses of 1.0 mg/kg (studied in anesthesia contexts) increase hallucinations to 28% and nightmares to 15%. 1
Psychotomimetic and dissociative effects are dose-dependent, making doses above 0.5 mg/kg inappropriate for psychiatric treatment. 2
Alternative Infusion Rates
While 0.5 mg/kg over 40 minutes is standard, slower infusion rates such as 0.5 mg/kg over 100 minutes may provide similar efficacy with potentially better tolerability, though this remains less studied. 1
The dose remains 0.5 mg/kg maximum regardless of infusion duration.
Dosing Range in Clinical Practice
Real-world Canadian data from 164 patients with treatment-resistant depression used 0.5-0.75 mg/kg over 40 minutes for four infusions over two weeks. 4
However, 0.75 mg/kg exceeds standard guideline recommendations and should be considered off-protocol; the evidence base strongly supports 0.5 mg/kg as the maximum. 1, 2
Symptomatic worsening occurred in only 1.83-5.49% of patients at standard doses, comparable to conventional antidepressants. 4
Patient Selection Requirements
Before administering ketamine at any dose, verify:
At least 2 adequate antidepressant trials have failed (adequate = therapeutic dose for ≥4-6 weeks). 1
For bipolar depression, concurrent mood stabilizer therapy (lithium or valproate) is mandatory to mitigate manic switch risk. 1
Esketamine (intranasal formulation) requires REMS certification and mandatory 2-hour post-treatment monitoring. 1, 2
Common Pitfalls to Avoid
Do not use doses above 0.5 mg/kg based on anesthesia literature; psychiatric dosing differs fundamentally from anesthetic dosing.
Do not administer without concurrent antidepressant therapy in most cases; ketamine functions best as augmentation rather than monotherapy. 5
Do not assume long-term safety is established; most evidence comes from acute treatment courses, and optimal maintenance strategies remain poorly defined. 1, 2
Antidepressant effects typically persist 2-3 days after single infusion, with significant improvements through day 7 when added to ongoing treatment. 1