Intravenous Ketamine for Treatment‑Resistant Major Depressive Disorder

Patient Qualification

The 2022 VA/DoD clinical practice guideline recommends ketamine or esketamine for patients who have failed several adequate pharmacologic trials, defining treatment resistance as lack of response to at least two antidepressants (e.g., sertraline 200 mg, bupropion 75 mg) plus augmentation agents such as quetiapine 50 mg and lamotrigine 200 mg. Evidence level: high (multiple RCTs and meta‑analyses). 1

The evidence‑based standard dose is intravenous ketamine 0.5 mg/kg infused over 40 minutes, administered twice weekly for a total of 4–6 infusions, as an add‑on to the patient’s existing antidepressant regimen. Evidence level: high (multiple RCTs and meta‑analyses). 1
Clinical response is typically observed within 24 hours after an infusion, with the antidepressant effect lasting 3–4 days per dose. Evidence level: moderate (RCTs). 1

Ongoing antidepressant and mood‑stabilizer medications should be continued during ketamine treatment; meta‑analysis of 20 randomized controlled trials demonstrated that ketamine added to existing antidepressant therapy produces significant symptom improvement lasting up to 7 days. Evidence level: high (meta‑analysis). 1
Lower‑dose ketamine (0.2–0.25 mg/kg) is supported only for emergency‑department use in patients with acute suicidal ideation and is not recommended for standard treatment‑resistant depression protocols. Evidence level: moderate (single‑center RCTs). 2

In treatment‑resistant populations, a series of six infusions yields a response rate of approximately 42 % and a remission rate of 14–17 % (based on pooled trial data). Evidence level: moderate (RCT aggregates). 1
The antidepressant benefit of a single infusion generally wanes after about one week; without a maintenance plan, most responders relapse within two weeks after the final infusion. Evidence level: moderate (follow‑up data from RCTs). 1

Common acute adverse effects at the 0.5 mg/kg dose include transient dissociation, nausea, ataxia, and modest blood‑pressure elevation; psychotomimetic symptoms (e.g., hallucinations, nightmares) occur in roughly 20 % and 12 % of patients, respectively, and resolve quickly after the infusion. Evidence level: moderate (RCT safety reports). 1

Intranasal esketamine is FDA‑approved for treatment‑resistant depression but requires REMS certification for the pharmacy and treatment site, as well as mandatory 2‑hour post‑administration monitoring. Evidence level: high (FDA‑approved protocol). 1
When used twice weekly as augmentation, esketamine improves response and remission rates by about 16 % at four weeks and has more robust evidence for long‑term maintenance compared with IV ketamine. Evidence level: high (phase III trials). 1

Do not use ketamine as monotherapy. The strongest evidence supports its role as an augmentation agent to ongoing antidepressants. Evidence level: high (meta‑analysis). [2][1]
Do not expect sustained remission without a maintenance strategy. Current data demonstrate only short‑term (≈7‑day) efficacy; planning for continuation (e.g., transition to esketamine or continued twice‑weekly infusions) is essential. Evidence level: moderate. 1

Transition to intranasal esketamine for maintenance is advisable when an acute response to IV ketamine is achieved, given its stronger long‑term efficacy data. Evidence level: high. 1
Continuing twice‑weekly IV ketamine infusions for responders is an alternative, although long‑term safety data remain limited. Evidence level: moderate. 1

The American College of Physicians suggests that intravenous ketamine at a dose of 0,5 mg/kg infused over 40 minutes demonstrates significant improvement in depressive symptoms in patients with treatment-resistant depression (TRD) after 24 hours, with effects lasting for 3-4 days 3, 4
A meta-analysis of 20 randomized controlled trials showed that intravenous ketamine as monotherapy or in combination with antidepressants results in significant improvement in depressive symptoms for up to 7 days when added to ongoing antidepressant treatment 3, 4
The American Medical Association notes that esketamine intranasal administration twice a week as an adjunctive therapy to ongoing oral antidepressants improves depressive symptoms and remission rates in patients with TRD for up to 28 days of follow-up 3, 4
Esketamine is also approved for the treatment of depressive symptoms in adults with depression and acute suicidal ideation or behavior 3, 4

The National Institute of Mental Health indicates that intravenous ketamine lacks long-term efficacy and safety studies in major depression, with most evidence on short-term efficacy (7 days) 3, 4
Common adverse effects of intravenous ketamine include nausea, ataxia, transient dissociation, and increased blood pressure 5
The incidence of laryngospasm is very low (0.9-1.4%) when used for sedation 6
The American Academy of Emergency Medicine notes that esketamine has requirements for risk evaluation and mitigation strategy, including requirements for pharmacy, healthcare setting certification, and mandatory monitoring for 2 hours after treatment 3, 4

Neither intravenous ketamine nor esketamine is recommended as initial treatment, being reserved for patients who have not responded to previous therapies or who have not tolerated previous therapies 3, 4
Intravenous ketamine and esketamine are suggested treatment options in patients who have not responded to several adequate pharmacological trials 3, 4
Intravenous ketamine may be particularly valuable for patients with acute suicidal ideation, given its rapid onset of action 7